Publications by authors named "Wonshik Han"

301 Publications

Clinical Outcomes Following Letrozole Treatment according to Estrogen Receptor Expression in Postmenopausal Women: LETTER Study (KBCSG-006).

J Breast Cancer 2021 Mar 25. Epub 2021 Mar 25.

Department of Surgery, Gangnam Severance Hospital, Seoul, Korea.

Purpose: In this trial, we investigated the efficacy and safety of adjuvant letrozole for hormone receptor (HR)-positive breast cancer. Here, we report the clinical outcome in postmenopausal women with HR-positive breast cancer treated with adjuvant letrozole according to estrogen receptor (ER) expression levels.

Methods: In this multi-institutional, open-label, observational study, postmenopausal patients with HR-positive breast cancer received adjuvant letrozole (2.5 mg/daily) for 5 years unless they experienced disease progression or unacceptable toxicity or withdrew their consent. The patients were stratified into the following 3 groups according to ER expression levels using a modified Allred score (AS): low, intermediate, and high (AS 3-4, 5-6, and 7-8, respectively). ER expression was centrally reviewed. The primary objective was the 5-year disease-free survival (DFS) rate.

Results: Between April 25, 2010, and February 5, 2014, 440 patients were enrolled. With a median follow-up of 62.0 months, the 5-year DFS rate in all patients was 94.2% (95% confidence interval [CI], 91.8-96.6). The 5-year DFS and recurrence-free survival (RFS) rates did not differ according to ER expression; the 5-year DFS rates were 94.3% and 94.1%in the low-to-intermediate and high expression groups, respectively ( = 0.6), and the corresponding 5-year RFS rates were 95.7% and 95.4%, respectively ( = 0.7). Furthermore, 25 patients discontinued letrozole because of drug toxicity.

Conclusion: Treatment with adjuvant letrozole showed very favorable treatment outcomes and good tolerability among Korean postmenopausal women with ER-positive breast cancer, independent of ER expression.

Trial Registration: ClinicalTrials.gov Identifier: NCT01069211.
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http://dx.doi.org/10.4048/jbc.2021.24.e17DOI Listing
March 2021

15-Deoxy-Δ-prostaglandin J Upregulates VEGF Expression via NRF2 and Heme Oxygenase-1 in Human Breast Cancer Cells.

Cells 2021 Mar 2;10(3). Epub 2021 Mar 2.

Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea.

There is a plethora of evidence to support that inflammation is causally linked to carcinogenesis. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandins, is inappropriately overexpressed in various cancers and hence recognized as one of the hallmarks of chronic inflammation-associated malignancies. However, the mechanistic role of COX-2 as a link between inflammation and cancer remains largely undefined. In this study, we found that 15-deoxy-Δ-prostaglandin J (15d-PGJ), one of the final products of COX-2, induced upregulation of vascular endothelial growth factor (VEGF) and capillary formation and migration through nuclear factor erythroid 2-related factor 2 (NRF2)-dependent heme oxygenase-1 (HO-1) induction in MCF-7 cells. Analysis of the publicly available TCGA data set showed that high mRNA levels of both COX-2 and NRF2 correlated with the poor clinical outcomes in breast cancer patients. Moreover, human tissue analysis showed that the levels of 15d-PGJ as well the expression of COX-2, NRF2, and HO-1 were found to be increased in human breast cancer tissues. In conclusion, the elevated levels of 15d-PGJ during inflammatory response activate VEGF expression through NRF2-driven induction of HO-1 in human breast cancer cells, proposing a novel mechanism underlying the oncogenic function of 15d-PGJ.
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http://dx.doi.org/10.3390/cells10030526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002112PMC
March 2021

The Emotional Status, Attitudes in Decision-Making Process, and Their Impact on Surgical Choices in Korean Breast Cancer Patients.

J Oncol 2021 12;2021:6636986. Epub 2021 Mar 12.

Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.

Purpose: We examined the incidence of emotional distress in women with newly diagnosed breast cancer to determine whether the degree of emotional distress affected their choice of breast-conserving surgery (BCS) or mastectomy and evaluated how the patient's preferred role in decision-making influenced her choice of surgical method.

Methods: This prospective study included 85 patients newly diagnosed with in situ or invasive breast cancer eligible for BCS. Their degree of depression/anxiety and attitude toward the decision-making process were measured using the Hospital Anxiety and Depression Scale (HADS) and Control Preference Scale (CPS), respectively. After receiving information on both surgical methods, the patients indicated their preferred surgical method and completed the CPS at their initial and second visits before surgery.

Results: After the diagnosis of breast cancer, 75.3% of patients showed abnormal or borderline HADS scores for depression and 41.2% for anxiety. Patients with borderline or abnormal degrees of depression were more likely to have coexisting abnormal degrees of anxiety ( < 0.001). However, the presence of depression or anxiety was not associated with patients' surgical choices (=0.394 and 0.530, respectively). Patients who preferred a more active role in the decision-making process were more likely to choose mastectomy over BCS, while those who were passive or collaborative chose BCS more frequently (=0.001).

Conclusion: Although many patients with newly diagnosed breast cancer experience depression and anxiety before surgery, these do not affect the choice of surgical method; however, their attitudes toward the decision-making process do.
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http://dx.doi.org/10.1155/2021/6636986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984876PMC
March 2021

Correlation between bone mineral density and endometrial thickness over time in women with breast cancer history.

Sci Prog 2021 Jan-Mar;104(1):368504211000515

Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul, South Korea.

As the efficacy of chemotherapy and adjuvant endocrine therapy for breast cancer increase, the quality-of-life to cancer survivors could be more important issue in strategies of breast cancer treatment. Bone health has become more compelling in care of breast cancer survivor than ever before. This retrospective study was aimed to evaluate factors relating to the change in BMD and to ascertain the correlation between changes in BMD and EMT of women with breast cancer in follow-up. Records of 164 women who underwent surgery for breast cancer were reviewed in this study. The basal characteristics included parity, menopausal state, medication with vitamin D, bisphosphonate, selective estrogen modulator (SERM), aromatase inhibitor (AI), gonadotrophin releasing hormone agonist (GnRHa), chemotherapy, radiotherapy, cancer type including positivity of estrogen receptor, progesterone receptor and HER2, combined the other gynecologic disease or the other origin cancer. At initial and follow-up visit, all subjective were checked with BMD, endometrial thickness (EMT). The mean age was 52.1 ± 8.5 years old and overall interval between initial and follow-up visits were 17.6 ± 7.5 month in this study. The BMDs of L1-4 (1.040 ± 0.166 g/cm vs 1.070 ± 0.181 g/cm,  < 0.001), femur neck (0.850 ± 0.121 g/cm vs 0.870 ± 0.136 g/cm,  < 0.001), and femur total (0.902 ± 0.132 g/cm vs 0.915 ± 0.138 g/cm,  < 0.001) at follow-up visit were significantly lower than those at initial visit. The change in BMDs of L1-4 (BMD,  = 0.353,  < 0.001, and  = 0.228,  = 0.003), femur neck (BMD,  = 0.198,  = 0.011, and  = 0.282,  < 0.001), femur total (BMD,  = 0.294,  < 0.001, and  = 0.327,  < 0.001) had positive correlation with age and the change in EMT (EMT). After age correction, EMT had positive correlation with BMD ( = 0.245,  = 0.002) and BMD ( = 0.273,  < 0.001). BMD and BMD differed according to menopausal state ( < 0.001 and  = 0.035), bisphosphonate ( < 0.001 and  < 0.001), and GnRHa ( < 0.001 and  < 0.001). In follow-up of women with history of breast cancer, EMT could be an alternative screening marker for BMD decrease.
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http://dx.doi.org/10.1177/00368504211000515DOI Listing
March 2021

Association between Number of Retrieved Sentinel Lymph Nodes and Breast Cancer-related Lymphedema.

J Breast Cancer 2021 Feb;24(1):63-74

Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Sentinel lymph node biopsy (SLNB) has become a standard axillary staging surgery for early breast cancer, and the proportion of patients requiring axillary lymph node dissection (ALND) is decreasing. We aimed to evaluate the association between the number of sentinel lymph nodes (SLNs) retrieved and the risk of lymphedema of the ipsilateral arm.

Methods: Prospectively collected medical records of 910 patients were reviewed. Lymphedema was defined as a difference in circumference > 2 cm compared to the contralateral arm and/or having clinical records of lymphedema treatment in the rehabilitation clinic.

Results: Together with an objective and subjective assessment of lymphedema, 36 patients (6.1%) had lymphedema in the SLNB group and 85 patients (27.0%) had lymphedema in the ALND group ( < 0.001). In a multivariate analysis of the whole cohort, risk factors significantly associated risk with the development of lymphedema were body mass index, mastectomy (vs. breast-conserving surgery), ALND, and radiation therapy. In logistic regression models in the SLNB group only, there was no correlation between the number of retrieved SLNs and the incidence of lymphedema. In addition, in the Pearson correlation analysis, no correlation was observed between the number of retrieved SLNs and the difference in circumference between the ipsilateral and contralateral upper extremities (correlation coefficients = 0.067, =0.111).

Conclusion: The risk of lymphedema in breast cancer surgery and adjuvant treatments is multifactorial. The number of retrieved lymph nodes during sentinel biopsy was not associated with the incidence of lymphedema.
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http://dx.doi.org/10.4048/jbc.2021.24.e9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920859PMC
February 2021

Is mastectomy with immediate reconstruction safe for patients undergoing neoadjuvant chemotherapy? A nationwide study from Korean Breast Cancer Society.

Breast Cancer 2021 Feb 14. Epub 2021 Feb 14.

Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea.

Purpose: In this study, we compared the prognoses of patients who underwent mastectomy with immediate breast reconstruction (IBR) after neoadjuvant chemotherapy with those who underwent mastectomy.

Methods: This retrospective study included 87,995 patients who were surgically treated for primary breast cancer between 2008 and 2014. We compared the three groups of patients who were divided based on the following surgeries: breast-conserving surgery (BCS), mastectomy, and mastectomy with IBR.

Results: Of the 3295 patients who were treated with neoadjuvant chemotherapy, 482 patients achieved a pathological complete response (pCR) and 2813 patients did not (non-pCR). In survival analysis of the pCR patients, the 5-year Overall Survival (5 yr OS) between those who underwent mastectomy with IBR and mastectomy (P = 0.639) In the non-pCR group, 5 yr OS of the mastectomy with IBR group was 90.0%, while those of the mastectomy group was 84.4% in patients with clinical stage II (P = 0.032). In a multivariate analysis by Cox regression method revealed that the prognoses of the patients who underwent mastectomy with IBR were not different from those of patients who underwent mastectomy group in both groups (the pCR group and the non-pCR group).

Conclusion: In the pCR group, the prognoses of patients who underwent mastectomy with IBR were not different from those of patients who underwent mastectomy. In the non-pCR group, women in the mastectomy with IBR group had shown worse prognoses than the mastectomy group in advanced clinical stage. Appropriate operation should be determined depending on the status of individualized patients.
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http://dx.doi.org/10.1007/s12282-021-01223-2DOI Listing
February 2021

S100A8/A9 mediate the reprograming of normal mammary epithelial cells induced by dynamic cell-cell interactions with adjacent breast cancer cells.

Sci Rep 2021 Jan 14;11(1):1337. Epub 2021 Jan 14.

Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.

To understand the potential effects of cancer cells on surrounding normal mammary epithelial cells, we performed direct co-culture of non-tumorigenic mammary epithelial MCF10A cells and various breast cancer cells. Firstly, we observed dynamic cell-cell interactions between the MCF10A cells and breast cancer cells including lamellipodia or nanotube-like contacts and transfer of extracellular vesicles. Co-cultured MCF10A cells exhibited features of epithelial-mesenchymal transition, and showed increased capacity of cell proliferation, migration, colony formation, and 3-dimensional sphere formation. Direct co-culture showed most distinct phenotype changes in MCF10A cells followed by conditioned media treatment and indirect co-culture. Transcriptome analysis and phosphor-protein array suggested that several cancer-related pathways are significantly dysregulated in MCF10A cells after the direct co-culture with breast cancer cells. S100A8 and S100A9 showed distinct up-regulation in the co-cultured MCF10A cells and their microenvironmental upregulation was also observed in the orthotropic xenograft of syngeneic mouse mammary tumors. When S100A8/A9 overexpression was induced in MCF10A cells, the cells showed phenotypic features of directly co-cultured MCF10A cells in terms of in vitro cell behaviors and signaling activities suggesting a S100A8/A9-mediated transition program in non-tumorigenic epithelial cells. This study suggests the possibility of dynamic cell-cell interactions between non-tumorigenic mammary epithelial cells and breast cancer cells that could lead to a substantial transition in molecular and functional characteristics of mammary epithelial cells.
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http://dx.doi.org/10.1038/s41598-020-80625-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809201PMC
January 2021

STAT3 Stabilizes IKKα Protein through Direct Interaction in Transformed and Cancerous Human Breast Epithelial Cells.

Cancers (Basel) 2020 Dec 30;13(1). Epub 2020 Dec 30.

Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Korea.

Signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are two representative transcription factors that play a critical role in inflammation-associated tumorigenesis through multi-level cooperation. Unlike other types of tumors, breast carcinomas have shown a significant dependency on the non-classical NF-κB pathway as well as the classical one. The α subunit of the inhibitor of the κB kinase (IKK) complex, IKKα, is involved in both classical and non-classical activation of NF-κB. Although the cross-talk between STAT3 and NF-κB has been suggested in several studies, the interplay between STAT3 and the regulators of NF-κB including IKKα has not been fully clarified yet. In this study, we observed overexpression and co-localization of IKKα and STAT3 in human breast cancer tissues as well as in H- transformed human breast epithelial (H- MCF-10A) and breast cancer (MDA-MB-231) cells. By utilizing small interfering RNA (siRNA) technology, we were able to demonstrate that STAT3 up-regulated IKKα, but not IKKβ or IKKγ, in these cells. This was attributable to direct binding to and subsequent stabilization of IKKα protein by blocking the ubiquitin-proteasome system. Notably, we identified the lysine 44 residue of IKKα as a putative binding site for STAT3. Moreover, siRNA knockdown of attenuated viability, anchorage-independent growth and migratory capabilities of H- MCF-10A cells. Taken together, these findings propose a novel mechanism responsible for NF-κB activation by STAT3 through stabilization of IKKα, which contributes to breast cancer promotion and progression. Thus, breaking the STAT3-IKKα alliance can be an alternative therapeutic strategy for the treatment of breast cancer.
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http://dx.doi.org/10.3390/cancers13010082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795115PMC
December 2020

Hypofractionated versus conventional fractionated radiotherapy for breast cancer in patients with reconstructed breast: Toxicity analysis.

Breast 2021 Feb 1;55:37-44. Epub 2020 Dec 1.

Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Republic of Korea; Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. Electronic address:

Purpose: This study investigated whether hypofractionated adjuvant radiotherapy (RT) increased breast-related complication(s) compared to conventional fractionated RT in reconstructed breast cancer patients.

Methods: We conducted a retrospective review including 349 breast cancer patients who underwent immediate breast reconstruction following mastectomy or breast-conserving surgery (BCS) between 2009 and 2018 at two institutions. All patients were treated with adjuvant RT via either a conventional fractionated or hypofractionated regimen. We defined a major breast complication as a breast-related toxic event requiring re-operation or re-hospitalization during the follow-up period after the end of RT.

Results: The median follow-up was 32.3 months (4.8-118.5 months); 126 patients had conventional fractionated RT, and 223 patients received hypofractionated RT. In patients with mastectomy, there was no significant difference in the occurrence of any or major breast-related complications between the two fractionation regimens. In patients undergoing BCS, incidence of any breast complication showed no difference between two RT groups and no major breast complication was reported as well. Hypofractionated RT did not increase major wound problem (infection and dehiscence) compared to conventional RT. Incidence of major contracture was significantly lower in hypofractionated RT.

Conclusions: There was no significant difference in the occurrence of any or major breast-related complications between the two different fractionation regimens, even in patients with mastectomy. Hypofractionated RT may be used comparable to conventional fractionated RT in terms of breast-related complications in reconstructed breast cancer patients. The prospective randomized trial would be necessary to clarify this issue.
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http://dx.doi.org/10.1016/j.breast.2020.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744765PMC
February 2021

Identification of breast cancer patients with pathologic complete response in the breast after neoadjuvant systemic treatment by an intelligent vacuum-assisted biopsy.

Eur J Cancer 2021 Jan 8;143:134-146. Epub 2020 Dec 8.

Department of Gynecology, Heidelberg University, Heidelberg, Germany. Electronic address:

Background: Neoadjuvant systemic treatment elicits a pathologic complete response (pCR) in about 35% of women with breast cancer. In such cases, breast surgery may be considered overtreatment. We evaluated multivariate algorithms using patient, tumor, and vacuum-assisted biopsy (VAB) variables to identify patients with breast pCR.

Methods: We developed and tested four multivariate algorithms: a logistic regression with elastic net penalty, an Extreme Gradient Boosting (XGBoost) tree, Support Vector Machines (SVM), and neural network. We used data from 457 women, randomly partitioned into training and test set (2:1), enrolled in three trials with stage 1-3 breast cancer, undergoing VAB before surgery. False-negative rate (FNR) and specificity were the main outcome measures. The best performing algorithm was validated in an independent fourth trial.

Results: In the test set (n = 152), the logistic regression with elastic net penalty, XGboost tree, SVM, and neural network revealed an FNR of 1.2% (1 of 85 patients with missed residual cancer). Specificity of the logistic regression with elastic net penalty was 52.2% (35 of 67 women with surgically confirmed breast pCR identified), of the XGBoost tree 55.2% (37 of 67), of SVM 62.7% (42 of 67), and of the neural network 67.2% (45 of 67). External validation (n = 50) of the neural network showed an FNR of 0% (0 of 27) and a specificity of 65.2% (15 of 23). Area under the ROC curve for the neural network was 0.97 (95% CI, 0.94-1.00).

Conclusion: A multivariate algorithm can accurately select breast cancer patients without residual cancer after neoadjuvant treatment.
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http://dx.doi.org/10.1016/j.ejca.2020.11.006DOI Listing
January 2021

Interaction of Nrf2 with dimeric STAT3 induces IL-23 expression: Implications for breast cancer progression.

Cancer Lett 2021 Mar 3;500:147-160. Epub 2020 Dec 3.

Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea; Cancer Research Institute, Seoul National University, Seoul, 03080, South Korea. Electronic address:

Persistent activation of STAT3 and Nrf2 is considered to stimulate the aggressive behavior of basal-like breast cancer (BLBC). However, the precise mechanism underlying sustained overactivation of these transcription factors and their roles in breast cancer progression remain elusive. Analysis of the TCGA multi-omics data showed that high levels of STAT3 and Nrf2 mRNA were correlated with elevated expression of P-STAT3 and Nrf2 target proteins in breast cancer patients. Our present study demonstrates a unique interaction between Nrf2 and STAT3 in the maintenance and progression of BLBC. RNA sequencing analysis identified the gene encoding IL-23A upregulated by concurrent binding of STAT3 and Nrf2 to its promoter. IL-23A depletion also showed the similar phenotypic changes to those caused by double knockdown of both transcription factors. In conclusion, the STAT3-Nrf2 interaction accelerates BLBC growth and progression by augmenting IL-23A expression, which underscores the importance of subtype-specific molecular pathways in human breast cancer.
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http://dx.doi.org/10.1016/j.canlet.2020.11.047DOI Listing
March 2021

Inhibition of Chk1 by miR-320c increases oxaliplatin responsiveness in triple-negative breast cancer.

Oncogenesis 2020 Oct 11;9(10):91. Epub 2020 Oct 11.

Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.

Checkpoint kinase 1 (Chk1) expression is enhanced in most cancers owing to oncogenic activation and constant replicative stress. Chk1 inactivation is a promising cancer therapy, as its inactivation leads to genomic instability, chromosomal catastrophe, and cancer cell death. Herein, we observed that miR-320c, downregulated in triple-negative breast cancer (TNBC) patients, can target Chk1. In addition, downregulated miR-320c expression was associated with poor overall survival in TNBC patients. As Chk1 was associated with the DNA damage response (DDR), we investigated the effect of miR-320c on DDR in TNBC cells. To induce DNA damage, we used platinum-based drugs, especially oxaliplatin, which is most effective with miR-320c. We observed that overexpression of miR-320c in TNBC regulated the oxaliplatin responsiveness by mediating DNA damage repair through the negative regulation of Chk1 in vitro. Furthermore, using a xenograft model, a combination of miR-320c mimic and oxaliplatin effectively inhibited tumor progression. These investigations indicate the potential of miR-320c as a marker of oxaliplatin responsiveness and a therapeutic target to increase the efficacy of chemotherapy in TNBC.
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http://dx.doi.org/10.1038/s41389-020-00275-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548284PMC
October 2020

Breast cancer cell debris diminishes therapeutic efficacy through heme oxygenase-1-mediated inactivation of M1-like tumor-associated macrophages.

Neoplasia 2020 11 8;22(11):606-616. Epub 2020 Oct 8.

Cancer Research Institute, Seoul National University, Seoul 03087, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University, Seoul 08826, South Korea. Electronic address:

Chemotherapy is commonly used as a major therapeutic option for breast cancer treatment, but its efficacy is often diminished by disruption of patient's anti-tumor immunity. Chemotherapy-generated tumor cell debris could hijack accumulated tumor-associated macrophages (TAMs), provoking tumor recurrence. Therefore, reprogramming TAMs to acquire an immunocompetent phenotype is a promising strategy to potentiate therapeutic efficacy. In this study, we analyzed the proportion of immune cells in the breast cancer patients who received chemotherapy. To validate our findings in vivo, we used a syngeneic murine breast cancer (4T1) model. Chemotherapy generates an immunosuppressive tumor microenvironment in breast cancer. Here, we show that phagocytic engulfment of tumor cell debris by TAMs reduces chemotherapeutic efficacy in a 4T1 breast cancer model. Specifically, the engulfment of tumor cell debris by macrophages reduced M1-like polarization through heme oxygenase-1 (HO-1) upregulation. Conversely, genetic or pharmacologic inhibition of HO-1 in TAMs restored the M1-like polarization. Our results demonstrate that tumor cell debris-induced HO-1 expression in macrophages regulates their polarization. Inhibition of HO-1 overexpression in TAMs may provoke a robust anti-tumor immune response, thereby potentiating the efficacy of chemotherapy.
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http://dx.doi.org/10.1016/j.neo.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581991PMC
November 2020

Development and Validation of a Next-Generation Sequencing-Based Multigene Assay to Predict the Prognosis of Estrogen Receptor-Positive, HER2-Negative Breast Cancer.

Clin Cancer Res 2020 Dec 7;26(24):6513-6522. Epub 2020 Oct 7.

Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.

Purpose: Multigene assays provide useful prognostic information regarding hormone receptor (HR)-positive breast cancer. Next-generation sequencing (NGS)-based platforms have numerous advantages including reproducibility and adaptability in local laboratories. This study aimed to develop and validate an NGS-based multigene assay to predict the distant recurrence risk.

Experimental Design: In total, 179 genes including 30 reference genes highly correlated with the 21-gene recurrence score (RS) algorithm were selected from public databases. Targeted RNA-sequencing was performed using 250 and 93 archived breast cancer samples with a known RS in the training and verification sets, respectively, to develop the algorithm and NGS-Prognostic Score (NGS-PS). The assay was validated in 413 independent samples with long-term follow-up data on distant metastasis.

Results: In the verification set, the NGS-PS and 21-gene RS displayed 91.4% concurrence (85/93 samples). In the validation cohort of 413 samples, area under the receiver operating characteristic curve plotted using NGS-PS values classified for distant recurrence was 0.76. The best NGS-PS cut-off value predicting distant metastasis was 20. Furthermore, 269 and 144 patients were classified as low- and high-risk patients in accordance with the cut-off. Five- and 10-year estimates of distant metastasis-free survival (DMFS) for low- versus high-risk groups were 97.0% versus 77.8% and 93.2% versus 64.4%, respectively. The age-related HR for distant recurrence without chemotherapy was 9.73 (95% CI, 3.59-26.40) and 3.19 (95% CI, 1.40-7.29) for patients aged ≤50 and >50 years, respectively.

Conclusions: The newly developed and validated NGS-based multigene assay can predict the distant recurrence risk in ER-positive, HER2-negative breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2107DOI Listing
December 2020

Accuracy of Post-Neoadjuvant Chemotherapy Image-Guided Breast Biopsy to Predict Residual Cancer.

JAMA Surg 2020 Oct 7:e204103. Epub 2020 Oct 7.

Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Importance: Image-guided breast biopsy of a residual imaging abnormality or tumor bed after neoadjuvant chemotherapy (NACT) is increasingly used to assess residual cancer, facilitate risk-adaptive surgery, and potentially identify exceptional responders in whom local therapy may be de-escalated.

Objective: To further assess the accuracy of post-NACT image-guided biopsy to predict residual cancer in the breast.

Design, Setting, And Participants: This diagnostic study analyzed multicenter patient-level data of patients with breast cancer who were treated with NACT and underwent image-guided biopsy before surgery at Royal Marsden Hospital in London, UK; Seoul National University Hospital in Seoul, South Korea; and MD Anderson Cancer Center in Houston, Texas. Data were analyzed from June to July 2019.

Main Outcomes And Measures: Diagnostic accuracy of post-NACT image-guided biopsy. Final surgical pathology was used as reference standard.

Results: Data from 166 women were analyzed. The median (range) age was 49 (25-76) years. The median (range) tumor size on pretreatment and posttreatment imaging was 33.5 (12-100) mm and 10 (0-100) mm, respectively. The overall pathologic complete response rate was 51.2% (n = 85) (16.1% [5 of 31] for hormone receptor-positive/ERBB2 (formerly HER2)-negative; 44.7% [21 of 47] for hormone receptor-positive/ERBB2-positive; 69% [20 of 29] for hormone receptor-negative/ERBB2-positive; and 66.1% [39 of 59] for triple negative). The majority (143 [86.1%]) underwent image-guided vacuum-assisted biopsy (VAB), and 23 had core-cut biopsy. The median (range) needle gauge was 10 (7-14), and the median (range) number of samples was 6 (2-18). When image-guided biopsy (VAB and core-cut biopsy) was representative (159 [95.8%]), the false-negative rate across the whole cohort was 18.7% (95% CI, 10.6%-29.3%). Subgroup analysis of patients with a complete/partial clinical response and residual imaging abnormality of 2 cm or smaller with at least 6 VABs taken (76 [45.8%]) demonstrated a false-negative rate of 3.2% (95% CI, 0.1%-16.7%), a negative predictive value of 97.4% (95% CI, 86.5%-99.9%), and an overall accuracy of 89.5% (95% CI, 80.3%-95.3%).

Conclusions And Relevance: This large multicenter pooled data analysis suggests that a standardized protocol using image-guided VAB of a tumor bed measuring 2 cm or smaller with 6 or more representative samples allows reliable prediction of residual disease. These results could inform the design of de-escalation trials in NACT exceptional responders testing the safety of eliminating surgery.
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http://dx.doi.org/10.1001/jamasurg.2020.4103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542519PMC
October 2020

Association of Insulin, Metformin, and Statin with Mortality in Breast Cancer Patients.

Cancer Res Treat 2021 Jan 23;53(1):65-76. Epub 2020 Sep 23.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Purpose: This study investigated the association of insulin, metformin, and statin use with survival and whether the association was modified by the hormone receptor status of the tumor in patients with breast cancer.

Materials And Methods: We studied 7,452 patients who had undergone surgery for breast cancer at Seoul National University Hospital from 2008 to 2015 using the nationwide claims database. Exposure was defined as a recorded prescription of each drug within 12 months before the diagnosis of breast cancer.

Results: Patients with prior insulin or statin use were more likely to be older than 50 years at diagnosis and had a higher comorbidity index than those without it (p < 0.01 for both). The hazard ratio (HR) for death with insulin use was 5.7 (p < 0.01), and the effect was attenuated with both insulin and metformin exposure with an HR of 1.2 (p=0.60). In the subgroup analyses, a heightened risk of death with insulin was further prominent with an HR of 17.9 (p < 0.01) and was offset by co-administration of metformin with an HR of 1.3 (p=0.67) in patients with estrogen receptor (ER)-negative breast cancer. Statin use was associated with increased overall mortality only in patients with ER-positive breast cancer with HR for death of 1.5 (p=0.05).

Conclusion: Insulin or statin use before the diagnosis of breast cancer was associated with an increase in all-cause mortality. Subsequent analyses suggested that metformin or statin use may have been protective in patients with ER-negative disease, which warrants further studies.
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http://dx.doi.org/10.4143/crt.2020.430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812023PMC
January 2021

Effects of tamoxifen and aromatase inhibitors on the risk of acute coronary syndrome in elderly breast cancer patients: An analysis of nationwide data.

Breast 2020 Dec 19;54:25-30. Epub 2020 Aug 19.

Department of Surgery, Seoul National University College of Medicine, 101 Daehakro, Jongno-gu, Seoul, Republic of Korea; Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, 101 Daehakro, Jongno-gu, Seoul, Republic of Korea. Electronic address:

Background: Aromatase inhibitors (AIs) are the preferred endocrine treatment for postmenopausal hormonal receptor-positive breast cancer. However, there is controversy on the long-term cardiovascular and cerebrovascular safety of AIs over that of tamoxifen.

Methods: We analyzed the National Health Information Database (NHID) of 281,255 women over a 20-year-old diagnosed with breast cancer between 2009 and 2016. Cardiovascular events (CVEs) were defined as the development of the following, acute coronary syndrome (ACS), ischemic and hemorrhagic stroke, defined by using insurance claim records. The model was constructed by Cox proportional hazard regression and this model was used to analyze the effects of AI and tamoxifen on CVE.

Results: We included 47,569 women for the final analysis. Patients were classified into 'No hormonal treatment (n = 18,807), 'Switch (n = 2097)', 'Tamoxifen (n = 7081)' and 'AI (n = 19,584)'. There were 2147 CVEs in 2032 patients (4.1%). Univariate analysis showed that women with tamoxifen had significantly lower risk for CVEs compared to no-treatment (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.74-0.97) while AI showed no such effect (HR 0.93, 95% CI 0.84-1.02). After adjusting for other risk factors (hypertension, dyslipidemia, family history), the use of tamoxifen was associated with significant protective effect against ACS (HR 0.63, 95% CI 0.47-0.84).

Conclusions: Our results, based on the NHID, supports the protective effect of tamoxifen against CVE in Korean breast cancer patients aged 55 and older that is not seen with AIs. Our results can guide the selection of adjuvant hormonal treatment agents for Korean breast cancer patients based on their risk of developing CVE.
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http://dx.doi.org/10.1016/j.breast.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481564PMC
December 2020

Effect of standard low-dose anthracycline chemotherapy on late congestive heart failure in breast cancer survivors aged between 50 and 59 at diagnosis: A nationwide study.

Breast 2020 Oct 31;53:125-129. Epub 2020 Jul 31.

Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

Objectives: Although chemotherapy-induced congestive heart failure (CHF) is a well-known adverse event in cancer survivors, the long-term risk of standard low-dose anthracycline has not yet been reported. This study aimed to investigate the long-term effects of standard anthracycline on late CHF in breast cancer survivors.

Materials And Methods: A nationwide retrospective cohort study was conducted using the national insurance claims data for nearly 98% of Korean citizens. Between Jan 2010 and Dec 2015, a total of 56,338 newly diagnosed female breast cancer survivors were included.

Results: The total number of person-years was 199,648 and the incidence rate of late CHF was 3.57 per 1000 person-years. In multivariate analysis according to the subject's age at diagnosis, only in the 50-59 age group, anthracycline-based [hazard ratio (HR) 1.765, 95% confidence interval (CI) 1.206-2.583] and taxane plus anthracycline-based regimens (HR 1.816, 95% CI 1.192-2.768) significantly increased the risk of late CHF. In the 50-59 age group, standard low-dose anthracycline significantly increased the risk of late CHF (HR 1.627, 95% CI 1.080-2.451) in Cox proportional hazard regression models. In competing risk model with recurrence and in-hospital death as competing risks, standard low-dose anthracycline was a significant risk factor for late CHF [subdistribution hazard ratio (SHR) 1.553, 95% CI 1.029-2.340].

Conclusion: This nationwide study showed that standard chemotherapy with low-dose anthracycline is a risk factor for late-onset CHF in breast cancer survivors who were in their 50 s at breast cancer diagnosis. Long-term monitoring of late CHF should be considered in these younger breast cancer survivors.
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http://dx.doi.org/10.1016/j.breast.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414012PMC
October 2020

H-Ras induces Nrf2-Pin1 interaction: Implications for breast cancer progression.

Toxicol Appl Pharmacol 2020 09 1;402:115121. Epub 2020 Jul 1.

Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea; Department of Molecular Medicine, Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea; Cancer Research Institute, Seoul National University, Seoul, South Korea. Electronic address:

Aberrant activation of H-Ras is often associated with tumor aggressiveness in breast cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1  (Pin1) is a unique enzyme that interacts with phosphorylated serine or threonine of a target protein and isomerizes the adjacent proline residue. Pin1 is prevalently overexpressed in human cancers, and its overexpression correlates with poor prognosis. Nuclear factor E2-related factor 2 (Nrf2) is a master regulator of cellular redox homeostasis. The sustained activation/accumulation of Nrf2 has been observed in many different types of human malignancies, conferring an advantage for growth and survival of cancer cells. The activated form of H-Ras (GTP-H-Ras) is highly overexpressed in human breast cancer tissues. In our present study, silencing of H-Ras decreased the invasiveness of MDA-MB-231 human breast cancer cells and abrogated the interaction between Pin1 and Nrf2 in these cells. Pin1 knockdown blocked the accumulation of Nrf2, thereby suppressing proliferation and clonogenicity of MCF10A-Ras human mammary epithelial cells. We found that Pin1 binds to Nrf2 which stabilizes this transcription factor by hampering proteasomal degradation. In conclusion, H-Ras activation in cooperation with the Pin1-Nrf2 complex represents a novel mechanism underlying breast cancer progression and constitutive activation of Nrf2 and can be exploited as a therapeutic target.
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http://dx.doi.org/10.1016/j.taap.2020.115121DOI Listing
September 2020

Effect of Timing of Gonadotropin-Releasing Hormone Agonist Administration for Ovarian Protection in Patients with Breast Cancer.

J Breast Cancer 2020 Jun 11;23(3):268-278. Epub 2020 May 11.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Purpose: This study was performed to investigate the effect of the interval between the start of gonadotropin-releasing hormone agonist (GnRHa) and the start of chemotherapy on ovarian protection in patients with breast cancer.

Methods: This was a prospective observational cohort study that included 136 patients with breast cancer below 40 years who received GnRHa during chemotherapy for fertility preservation. Plasma anti-Müllerian hormone (AMH) levels were measured before chemotherapy (baseline) and after chemotherapy. Subjects were divided into 3 groups according to the interval between the start of GnRHa and the start of chemotherapy for analysis: 1-6 days, 7-13 days, and ≥ 14 days. The ratio of the post-chemotherapy AMH value to the baseline AMH (pcAMH) at each time point were compared among the 3 groups. Ranked analysis of covariance was used for statistical analysis, adjusted for age, body mass index (BMI), and the existence of polycystic ovaries (PCOs). In addition, recovery of ovarian function (AMH ≥ 1 ng/mL) at 12 months was evaluated.

Results: The median age of the patients was 32 years. There was no difference in the baseline AMH levels among the 3 groups (mean ± standard error: 5.0 ± 0.4 ng/mL [1-6 days], 5.3 ± 0.7 ng/mL [7-13 days], and 8.1 ± 1.3 ng/mL [≥ 14 days]; = 0.250). The pcAMH at 3, 6, 12, 24, and 36 months were not significantly different among the 3 groups (-values were 0.332, 0.732, 0.830, 0.148, and 0.393, respectively). In multivariate analysis, young age ( = 0.024), low BMI ( = 0.013), and the existence of PCO ( = 0.015) were predictors for AMH ≥ 1 ng/mL at 12 months.

Conclusion: There was no difference in the ovarian protective effect according to the difference in the timing of administration of GnRHa.
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http://dx.doi.org/10.4048/jbc.2020.23.e33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311369PMC
June 2020

Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer.

Breast Cancer Res 2020 05 27;22(1):54. Epub 2020 May 27.

Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic ro 43 gil, song pa gu, Seoul, 138-736, South Korea.

Introduction: Neoadjuvant endocrine therapy (NET) has demonstrated efficacy in post-menopausal patients with hormone-responsive breast cancer. This trial was designed to compare the efficacy of neoadjuvant chemotherapy (NCT) with NET in pre-menopausal breast cancer.

Patients And Methods: In this prospective, randomised, phase III study, oestrogen receptor (ER)-positive, HER2-negative, and lymph node-positive pre-menopausal breast cancer patients were recruited from 7 hospitals in South Korea. Enrolled patients were randomly assigned (1:1) to receive 24 weeks of either NCT or NET with goserelin and tamoxifen. The primary purpose was to evaluate the non-inferiority of NET compared to NCT using clinical response, assessed by MRI. Besides, pathological complete response rate (pCR), changes in Ki-67 expression, breast conservation surgery (BCS) rate, and quality of life were included as secondary endpoints.

Results: A total of 187 patients were assigned to receive NCT (n = 95) or NET (n = 92), and 87 patients in each group completed treatments. More NCT patients had complete response or partial response than NET patients using MRI (NCT 83.7% vs. NET 52.9%, 95% CI 17.6-44.0, p < 0.001) and callipers (NCT 83.9% vs. NET 71.3%, 95% CI 0.4-24.9, p = 0.046). Three NCT patients (3.4%) and one NET patient (1.2%) showed pCR (p < 0.005). No difference existed in the conversion rate of BCS (13.8% for NCT vs. 11.5% for NET, p = 0.531) and Ki-67 change (p = 0.114) between the two groups. Nineteen NCT patients had treatment-related grade 3 or worse events compared with none in the NET group.

Conclusions: Better clinical responses were observed in pre-menopausal patients after 24 weeks of NCT compared to those observed after NET.

Trial Registration: Clinicaltrials.gov, NCT01622361. Registration June 19, 2012.
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http://dx.doi.org/10.1186/s13058-020-01288-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251809PMC
May 2020

Prediction of pathologic complete response using image-guided biopsy after neoadjuvant chemotherapy in breast cancer patients selected based on MRI findings: a prospective feasibility trial.

Breast Cancer Res Treat 2020 Jul 16;182(1):97-105. Epub 2020 May 16.

Department of Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Purpose: Accurate prediction of pathologic complete response (pCR) in breast cancer using magnetic resonance imaging (MRI) and ultrasound (US)-guided biopsy may aid in selecting patients who forego surgery for breast cancer. We evaluated the accuracy of US-guided biopsy aided by MRI in predicting pCR in the breast after neoadjuvant chemotherapy (NAC).

Methods: After completion of NAC, 40 patients with near pCR (either tumor size ≤ 0.5 cm or lesion-to-background signal enhancement ratio (L-to-B SER) ≤ 1.6 on MRI) and no diffused residual microcalcifications were prospectively enrolled at a single institution. US-guided multiple core needle biopsy (CNB) or vacuum-assisted biopsy (VAB) of the tumor bed, followed by standard surgical excision, was performed. Matched biopsy and surgical specimens were compared to assess pCR. The negative predictive value (NPV), accuracy, and false-negative rate (FNR) were analyzed.

Results: pCR was confirmed in 27 (67.5%) surgical specimens. Preoperative biopsy had an NPV, accuracy, and FNR of 87.1%, 90.0%, and 30.8%, respectively. NPV for hormone receptor-negative and hormone receptor-positive tumors were 83.3% and 100%, respectively. Obtaining at least 5 biopsy cores based on tumor size ≤ 0.5 cm and an L-to-B SER of ≤ 1.6 on MRI (27 patients) resulted in 100% NPV and accuracy. No differences in accuracy were noted between CNB and VAB (90% vs. 90%).

Conclusions: Investigation using stringent MRI criteria and ultrasound-guided biopsy could accurately predict patients with pCR after NAC. A larger prospective clinical trial evaluating the clinical safety of breast surgery omission after NAC in selected patients will be conducted based on these findings.
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http://dx.doi.org/10.1007/s10549-020-05678-3DOI Listing
July 2020

Protein Kinase A Catalytic Subunit Is a Molecular Switch that Promotes the Pro-tumoral Function of Macrophages.

Cell Rep 2020 05;31(6):107643

Macrophage Lab, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul 110-799, South Korea; Department of Biomedical Sciences and Seoul National University College of Medicine, Seoul 110-799, South Korea. Electronic address:

As current therapies benefit only a minority of cancer patients, additional therapeutic targets are needed. Tumor-associated macrophages (TAMs) have attracted attention for improving therapeutic responses, yet regulatory strategies remain elusive. Here, we show that the protein kinase A catalytic subunit (PKA-C) acts as a molecular switch, inducing a pro-tumoral immunosuppressive macrophage phenotype within tumors. In human and murine breast cancer, overactivated PKA in TAMs creates a detrimental microenvironment for cancer progression by inducing vascular endothelial growth factor A (VEGFA), interleukin-10 (IL-10), and macrophage-derived arginase 1 (ARG1) expression. Macrophages with genetic deletion of PKA-C are prone to be pro-inflammatory, suggesting a possible immunotherapeutic target. Delivery of liposomal PKA inhibitor facilitates tumor regression and abrogates pro-tumoral TAM functions in mice. The therapeutic effect of targeting PKA is pronounced when combined with αCTLA-4 antibody, increasing cluster of differentiation 8 (CD8)GranzymeB T cells by about 60-fold. Our findings demonstrate critical roles of TAM PKA-C in tumor progression and suggest that targeting PKA-C efficiently augments cancer treatment responses.
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http://dx.doi.org/10.1016/j.celrep.2020.107643DOI Listing
May 2020

Prognostic Role of Androgen Receptor Expression in Surgically Resected Early Breast Cancer Patients.

J Breast Cancer 2020 Apr 20;23(2):182-193. Epub 2020 Apr 20.

Cancer Research Institute, Seoul National University, Seoul, Korea.

Purpose: Endocrine therapy is a standard treatment for hormone receptor-positive breast cancer, which accounts for 60%-75% of all breast cancer. Hormone receptor positivity is a prognostic and predictive biomarker in breast cancer. Approximately 50%-80% of breast cancer is also positive for androgen receptor (AR), but the prognostic and predictive value of AR expression in breast cancer is controversial. Here, we investigated AR expression and its prognostic value in patients with surgically resected breast cancer in Korea.

Methods: We retrospectively reviewed the medical records of patients who had surgically resected breast cancer to collect AR expression data and other clinicopathological data. The optimal cut-off for AR positivity was determined using a receiver operating characteristic curve analysis.

Results: We reviewed 957 patients with surgically resected breast cancer from June 2012 to April 2013. The median follow-up was 62 months, and relapse events occurred in 101 (10.6%) patients. Unlike the cut-off value of 1% or 10% in previous reports, 35% was determined to be best for predicting relapse-free survival (RFS) in this study. At the cut-off value of 35%, 654 (68.4%) patients were AR-positive. AR expression was more prevalent in luminal A (87.6%) and luminal B (73.1%) types than in human epidermal growth factor receptor 2-positive (56.2%) or triple-negative (20.6%) types. AR expression of ≥ 35% was significantly related to longer RFS in a multivariate analysis (hazard ratio, 0.430; 95% confidence interval, 0.260-0.709; = 0.001).

Conclusion: We propose a cut-off value of 35% to best predict RFS in patients with surgically resected breast cancer. AR expression was positive in 68.4% of patients, and AR positivity was found to be an independent prognostic factor for longer RFS.
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http://dx.doi.org/10.4048/jbc.2020.23.e28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192742PMC
April 2020

Protein Phosphatase 1H, Cyclin-Dependent Kinase Inhibitor p27, and Cyclin-Dependent Kinase 2 in Paclitaxel Resistance for Triple Negative Breast Cancers.

J Breast Cancer 2020 Apr 9;23(2):162-170. Epub 2020 Mar 9.

Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.

Purpose: Paclitaxel is a cytotoxic chemotherapy commonly used in patients with triple negative breast cancer (TNBC); however, the resistance to paclitaxel is a cause of poor response in the patients. The aim of this study was to examine the role of protein phosphatase 1H (PPM1H) in paclitaxel resistance in breast cancer patients.

Methods: To investigate the function of PPM1H in paclitaxel treatment, we conducted assays and molecular experiments using a stable cell line (MDA-MB-231) in which PPM1H is overexpressed. We also performed molecular analyses on patient tissue samples. Molecular expression related to PPM1H in breast cancer patients was analyzed using TCGA data.

Results: We investigated whether PPM1H was associated with paclitaxel resistance in breast cancer. PPM1H expression was upregulated in breast cancer cells treated with paclitaxel. We also observed that overexpression of PPM1H in breast cancer cells resulted in increased sensitivity to paclitaxel . Additionally, paclitaxel treatment induced dephosphorylation of cyclin-dependent kinase (CDK) inhibitor p27 (p27), which was more evident in PPM1H-overexpressing cells. To understand how upregulation of PPM1H increases paclitaxel sensitivity, we determined the levels of p27, phospho-p27, and CDK2, since CDK2 exerts antagonistic effects against PPM1H on p27 phosphorylation. The patient-derived xenograft (PDX) tumors that did not respond to paclitaxel showed increased levels of CDK2 and phospho-p27 and decreased levels of total p27 compared to the other breast tumor tissues. The use of dinaciclib, a selective CDK inhibitor, significantly inhibited tumor growth in the PDX model.

Conclusion: CDK2 kinase activity was significantly upregulated in basal breast cancer tumors and was negatively correlated with p27 protein levels in the TCGA breast cancer dataset, suggesting that targeting CDK2 may be an effective treatment strategy for TNBC patients.
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http://dx.doi.org/10.4048/jbc.2020.23.e20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192749PMC
April 2020

NAD(P)-dependent steroid dehydrogenase-like is involved in breast cancer cell growth and metastasis.

BMC Cancer 2020 May 4;20(1):375. Epub 2020 May 4.

Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Background: The cholesterol biosynthesis pathway is typically upregulated in breast cancer. The role of NAD(P)-dependent steroid dehydrogenase-like (NSDHL) gene, which is involved in cholesterol biosynthesis, in breast cancer remains unknown. This study aimed to uncover the role of NSDHL in the growth and metastasis of breast cancer.

Methods: After NSDHL knockdown by transfection of short interfering RNA into human breast cancer cell lines (MCF-7, MDA-MB-231 and BT-20) and human breast epithelial cell line (MCF10A), cell proliferation assay, cell cycle analysis, three-dimensional cell culture, clonogenic assay, transwell migration and invasion assays, and wound healing assay were performed. Erlotinib was used as the target drug for epidermal growth factor receptor. Immunodeficient mice (NOD.Cg-Prkdcscid Il2rgtm1wjl /SzJ) were used as orthotropic breast tumor models by injecting them with NSDHL-knockdown MDA-MB-231 cells using lentivirus-carrying NSDHL short hairpin RNA. Clinical data from 3951 breast cancer patients in Gene Expression Omnibus databases were used to investigate the potential prognostic role of NSDHL by survival analysis.

Results: NSDHL knockdown in BT-20, and MDA-MB-231 resulted in a significant decrease in their viability, colony formation, migration, and invasion abilities (p < 0.05). Total cholesterol levels were observed to be significantly decreased in NSDHL-knockdown BT-20 and MDA-MB-231 (p < 0.0001). NSDHL knockdown significantly increased the rate of erlotinib-induced cell death, especially in MDA-MB-231 (p = 0.01). NSDHL knockdown led to significantly decreased tumor growth and lung metastasis in the MDA-MB-231 xenograft model (p < 0.01). Clinically, high NSDHL expression in tumors of patients with breast cancer was associated with significantly reduced recurrence-free survival (p < 0.0001).

Conclusions: NSDHL might have a role in promoting breast cancer progression. The usage of NSDHL as a therapeutic target in breast cancer needs to be clarified in further studies.
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http://dx.doi.org/10.1186/s12885-020-06840-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197182PMC
May 2020

A Review of the Epidemiology of Breast Cancer in Asia: Focus on Risk Factors.

Asian Pac J Cancer Prev 2020 Apr 1;21(4):867-880. Epub 2020 Apr 1.

Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Cancer Hospital, Republic of Korea.

Background And Aim: Breast cancer is the most prevalent cancer in women. To date, regional differences in breast cancer risk factors have not been identified. The aim of our review was to gain a better understanding of the role of risk factors in women with breast cancer in Asia.

Methods: We conducted a PubMed search on 15 March 2016, for journal articles published in English between 2011 and 2016, which reported data for human subjects in Asia with a diagnosis of breast cancer. Search terms included breast neoplasm, epidemiology, Asia, prevalence, incidence, risk and cost of illness. Studies of any design were included, except for review articles and meta-analyses, which were excluded to avoid duplication of data. No exclusions were made based on breast cancer treatment. We reported the results using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.

Results: A total of 776 abstracts were retrieved. After screening against the eligibility criteria, 562 abstracts were excluded. The remaining 214 abstracts, which were published between 2013 and 2015, were included in this review. Results were summarized and reported under three categories: incidence, prevalence or outcomes for breast cancer in Asia; modifiable risk factors; and non-modifiable risk factors. We found that the increased risk of breast cancer among participants from Asia was associated with older age, family history of breast cancer, early menarche, late menopause, high body mass index, being obese or overweight, exposure to tobacco smoke, and high dietary intake of fats or fatty foods. In contrast, intake of dietary fruits, vegetables, and plant- and soy-based products was associated with a decreased breast cancer risk. While based on limited data, when compared to women from the United States, women from Asia had a decreased risk of breast cancer.

Conclusions: This review of 214 abstracts of studies in Asia, published between 2013 and 2015, confirmed the relevance of known non-modifiable and modifiable risk factors for women with breast cancer.
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http://dx.doi.org/10.31557/APJCP.2020.21.4.867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445974PMC
April 2020

Efficacy of health coaching and a web-based program on physical activity, weight, and distress management among cancer survivors: A multi-centered randomised controlled trial.

Psychooncology 2020 07 23;29(7):1105-1114. Epub 2020 Apr 23.

Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.

Objectives: To investigate the efficacy of health coaching and a web-based program on survivor physical activity (PA), weight, and distress management among stomach, colon, lung and breast cancer patients.

Methods: This randomised, controlled, 1-year trial conducted in five hospitals recruited cancer survivors within 2 months of completing primary cancer treatment who had not met ≥1 of these behavioural goals: (i) conducting moderate PA for at least 150 minutes/week or strenuous exercise for over 75 minutes per week or, in the case of lung cancer patients, low or moderate intensity exercise for over 12.5 MET per week, (ii) maintaining normal weight, and (iii) attaining a score >72 in the Post Traumatic Growth Inventory (PTGI). Participants were randomly assigned to one of three groups: the control group, a web-only group, or a health coaching + web group. The primary endpoint was based on a composite of PA, weight, and PTGI score at 12 months.

Results: Patients in the health coaching + web group (difference = 6.6%, P = .010) and the web-only group (difference = 5.9%, P = .031) had greater overall improvements across the three-outcome composite than the control group. The health coaching + web group had greater overall improvement in PTGI (difference = 12.6%; P < .001) than the control group, but not in PA and weight.

Conclusion: The web-based program, with or without health coaching, may improve health behaviours including PA, weight, and distress management among cancer survivors within 2 months of completing primary cancer treatment. The web-based program with health coaching was mainly effective for reducing psychological distress.
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http://dx.doi.org/10.1002/pon.5394DOI Listing
July 2020

Erratum: A Validation Study of a Multiple Reaction Monitoring-Based Proteomic Assay to Diagnose Breast Cancer.

J Breast Cancer 2020 02 3;23(1):113-114. Epub 2020 Jan 3.

Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.

[This corrects the article on p. 579 in vol. 22, PMID: 31897331.].
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http://dx.doi.org/10.4048/jbc.2020.23.e6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043948PMC
February 2020

Transduction of an SV40-Immortalized Normal Human Thyroid Cell Line Induces Dedifferentiated Thyroid Carcinogenesis in a Mouse Xenograft Model.

Thyroid 2020 04;30(4):487-500

Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

Despite active studies of the clinical importance of BRAF, suitable research models to investigate the role of this mutation in the etiopathogenesis of human thyroid cancers are limited. Thus, we generated cell lines by transducing the simian virus (SV)-40 immortalized human thyroid cell line Nthy-ori 3-1 (Nthy) with lentiviral vectors expressing either (Nthy/WT) or . Nthy/WT and Nthy/V600E cells were then xenografted into mice to evaluate the carcinogenic role of BRAF. Each cell line was subcutaneously injected into NOD.Cg-Prkdc Il2rg/SzJ mice, and a pathological analysis was performed. The effects of the mutation were further verified by using a BRAF-selective inhibitor (PLX-4032, vemurafenib). The transcriptome was analyzed by RNA sequencing and compared with data from The Cancer Cell Line Encyclopedia and Gene Expression Omnibus. While Nthy/WT was not tumorigenic , Nthy/V600E formed tumors reaching 2784.343 mm in 4 weeks, on average. A pathological analysis indicated that Nthy/V600E tumors were dedifferentiated thyroid cancer. We found metastases in the lung, liver, and relevant lymph nodes. A transcriptomic analysis revealed 5512 differentially expressed genes (DEGs) between the mutant and wild-type cell lines, and more DEGs were shared with anaplastic thyroid cancer than with papillary thyroid cancer. BRAF activated the cell cycle mainly by regulating G1/S phases. PLX-4032 treatment significantly inhibited tumor growth and metastasis. Our data show that BRAF plays a pivotal role in the carcinogenic transformation of an SV40-transfected immortalized normal human thyroid cell line. This xenograft model is expected to contribute to studies of the etiopathogenesis and treatment of highly malignant thyroid cancers.
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http://dx.doi.org/10.1089/thy.2019.0301DOI Listing
April 2020