Publications by authors named "Joseph Geradts"

106 Publications

Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP) in Breast Cancer Is Associated with Shorter Survival and Resistance to Chemotherapy.

Cancers (Basel) 2021 Jun 4;13(11). Epub 2021 Jun 4.

Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 13009 Marseille, France.

XIAP, the most potent inhibitor of cell death pathways, is linked to chemotherapy resistance and tumor aggressiveness. Currently, multiple XIAP-targeting agents are in clinical trials. However, the characterization of XIAP expression in relation to clinicopathological variables in large clinical series of breast cancer is lacking. We retrospectively analyzed non-metastatic, non-inflammatory, primary, invasive breast cancer samples for mRNA ( = 2341) and protein ( = 367) expression. XIAP expression was analyzed as a continuous value and correlated with clinicopathological variables. mRNA expression was heterogeneous across samples and significantly associated with younger patients' age (≤50 years), pathological ductal type, lower tumor grade, node-positive status, HR+/HER2- status, and PAM50 luminal B subtype. Higher XIAP expression was associated with shorter DFS in uni- and multivariate analyses in 909 informative patients. Very similar correlations were observed at the protein level. This prognostic impact was significant in the HR+/HER2- but not in the TN subtype. Finally, mRNA expression was associated with lower pCR rate to anthracycline-based neoadjuvant chemotherapy in both uni- and multivariate analyses in 1203 informative patients. Higher XIAP expression in invasive breast cancer is independently associated with poorer prognosis and resistance to chemotherapy, suggesting the potential therapeutic benefit of targeting XIAP.
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http://dx.doi.org/10.3390/cancers13112807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200223PMC
June 2021

Race-Related Differences in the Clinical Presentation and Histopathologic Features of Phyllodes Tumor.

Am Surg 2021 Jun 30:31348211029841. Epub 2021 Jun 30.

Department of Surgery, 12278East Carolina University Brody School of Medicine, Greenville, NC, USA.

Background: Phyllodes tumor (PT) is a rare fibroepithelial lesion of the breast with variable malignant potential. Black women have a higher incidence of a related benign tumor, fibroadenoma, but there are limited epidemiological data on PT. The aim of our study was to evaluate race-related differences in the clinicopathologic features and outcomes of PT.

Methods: Our institutional pathology database was queried for breast specimen reports from 01/2009 to 10/2019 to identify patients with a pathologic diagnosis of PT. Chart review and detailed slide review were performed to obtain clinical and histopathologic variables, respectively.

Results: Among twelve patients, two had malignant PT, three had borderline PT, and seven had benign PT. All patients with malignant and borderline PT were black, compared with 29% of those with benign PT. There were no apparent race-related differences in specific histopathologic features among black vs. non-black women with benign PT. Malignant and borderline PT were relatively larger than benign PT, with mean tumor sizes of 9.0 cm (standard deviation [SD] 4.7 cm), 12.2 cm (SD 9.4 cm), and 5.4 cm (SD 5.8 cm), respectively. Two women had a local recurrence, both of whom were black.

Discussion: In this single-institution retrospective study, we observed disproportionate rates of aggressive histopathologic features and disparate outcomes among black women with PT. A multi-institutional PT registry would facilitate improved knowledge about race-related differences in the presentation and outcomes of this rare tumor.
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http://dx.doi.org/10.1177/00031348211029841DOI Listing
June 2021

Outcomes of Hormone-Receptor Positive, HER2-Negative Breast Cancers by Race and Tumor Biological Features.

JNCI Cancer Spectr 2021 Feb 23;5(1):pkaa072. Epub 2020 Sep 23.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Black women have higher hormone receptor positive (HR+) breast cancer mortality than White women. Early recurrence rates differ by race, but little is known about genomic predictors of early recurrence among HR+ women.

Methods: Using data from the Carolina Breast Cancer Study (phase III, 2008-2013), we estimated associations between race and recurrence among nonmetastatic HR+/HER2-negative tumors, overall and by PAM50 Risk of Recurrence score, PAM50 intrinsic subtype, and tumor grade using survival curves and Cox models standardized for age and stage. Relative frequency differences (RFD) were estimated using multivariable linear regression. To assess intervention opportunities, we evaluated treatment patterns by race among patients with high-risk disease.

Results: Black women had higher recurrence risk relative to White women (crude hazard ratio = 1.81, 95% confidence interval [CI] = 1.34 to 2.46), which remained elevated after standardizing for clinical covariates (hazard ratio = 1.42, 95% CI = 1.05 to 1.93). Racial disparities were most pronounced among those with high PAM50 Risk of Recurrence score (5-year standardized recurrence risk = 18.9%, 95% CI = 8.6% to 29.1% in Black women vs 12.5%, 95% CI = 2.0% to 23.0% in White women) and high grade (5-year standardized recurrence risk = 16.6%, 95% CI = 11.7% to 21.5% in Black women vs 12.0%, 95% CI = 7.3% to 16.7% in White women). However, Black women with high-grade tumors were statistically significantly less likely to initiate endocrine therapy (RFD = -8.3%, 95% CI = -15.9% to -0.6%) and experienced treatment delay more often than White women (RFD = +9.0%, 95% CI = 0.3% to 17.8%).

Conclusions: Differences in recurrence by race appear greatest among women with aggressive tumors and may be influenced by treatment differences. Efforts to identify causes of variation in cancer treatment are critical to reducing outcome disparities.
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http://dx.doi.org/10.1093/jncics/pkaa072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791616PMC
February 2021

Spatiotemporal strategies to identify aggressive biology in precancerous breast biopsies.

Wiley Interdiscip Rev Syst Biol Med 2020 Oct 1:e1506. Epub 2020 Oct 1.

Department of Population Sciences, City of Hope Comprehensive Cancer Center, Duarte, California, USA.

Over 90% of breast cancer is cured; yet there remain highly aggressive breast cancers that develop rapidly and are extremely difficult to treat, much less prevent. Breast cancers that rapidly develop between breast image screening are called "interval cancers." The efforts of our team focus on identifying multiscale integrated strategies to identify biologically aggressive precancerous breast lesions. Our goal is to identify spatiotemporal changes that occur prior to development of interval breast cancers. To accomplish this requires integration of new technology. Our team has the ability to perform single cell in situ transcriptional profiling, noncontrast biological imaging, mathematical analysis, and nanoscale evaluation of receptor organization and signaling. These technological innovations allow us to start to identify multidimensional spatial and temporal relationships that drive the transition from biologically aggressive precancer to biologically aggressive interval breast cancer. This article is categorized under: Cancer > Computational Models Cancer > Molecular and Cellular Physiology Cancer > Genetics/Genomics/Epigenetics.
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http://dx.doi.org/10.1002/wsbm.1506DOI Listing
October 2020

Quantitative assessment of distant recurrence risk in early stage breast cancer using a nonlinear combination of pathological, clinical and imaging variables.

J Biophotonics 2020 10 3;13(10):e201960235. Epub 2020 Aug 3.

Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.

Use of genomic assays to determine distant recurrence risk in patients with early stage breast cancer has expanded and is now included in the American Joint Committee on Cancer staging manual. Algorithmic alternatives using standard clinical and pathology information may provide equivalent benefit in settings where genomic tests, such as OncotypeDx, are unavailable. We developed an artificial neural network (ANN) model to nonlinearly estimate risk of distant cancer recurrence. In addition to clinical and pathological variables, we enhanced our model using intraoperatively determined global mammographic breast density (MBD) and local breast density (LBD). LBD was measured with optical spectral imaging capable of sensing regional concentrations of tissue constituents. A cohort of 56 ER+ patients with an OncotypeDx score was evaluated. We demonstrated that combining MBD/LBD measurements with clinical and pathological variables improves distant recurrence risk prediction accuracy, with high correlation (r = 0.98) to the OncotypeDx recurrence score.
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http://dx.doi.org/10.1002/jbio.201960235DOI Listing
October 2020

Androgen receptor with short polyglutamine tract preferably enhances Wnt/β-catenin-mediated prostatic tumorigenesis.

Oncogene 2020 04 24;39(16):3276-3291. Epub 2020 Feb 24.

Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA, 91010-3000, USA.

Polyglutamine (polyQ) tract polymorphism within the human androgen receptor (AR) shows population heterogeneity. African American men possess short polyQ tracts significantly more frequently than Caucasian American men. The length of polyQ tracts is inversely correlated with the risk of prostate cancer, age of onset, and aggressiveness at diagnosis. Aberrant activation of Wnt signaling also reveals frequently in advanced prostate cancer, and an enrichment of androgen and Wnt signaling activation has been observed in African American patients. Here, we assessed aberrant expression of AR bearing different polyQ tracts and stabilized β-catenin in prostate tumorigenesis using newly generated mouse models. We observed an early onset oncogenic transformation, accelerated tumor cell growth, and aggressive tumor phenotypes in the compound mice bearing short polyQ tract AR and stabilized β-catenin. RNA sequencing analysis showed a robust enrichment of Myc-regulated downstream genes in tumor samples bearing short polyQ AR versus those with longer polyQ tract AR. Upstream regulator analysis further identified Myc as the top candidate of transcriptional regulators in tumor cells from the above mouse samples with short polyQ tract AR and β-catenin. Chromatin immunoprecipitation analyses revealed increased recruitment of β-catenin and AR on the c-Myc gene regulatory locus in the tumor tissues expressing stabilized β-catenin and shorter polyQ tract AR. These data demonstrate a promotional role of aberrant activation of Wnt/β-catenin in combination with short polyQ AR expression in prostate tumorigenesis and suggest a potential mechanism underlying aggressive prostatic tumor development, which has been frequently observed in African American patients.
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http://dx.doi.org/10.1038/s41388-020-1214-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165053PMC
April 2020

DNA methylation markers predict recurrence-free interval in triple-negative breast cancer.

NPJ Breast Cancer 2020 31;6. Epub 2020 Jan 31.

1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA.

We lack tools to risk-stratify triple-negative breast cancer (TNBC). Our goal was to develop molecular tools to predict disease recurrence. Methylation array analysis was performed on 110 samples treated by locoregional therapy obtained from institutional cohorts. Discovered marker sets were then tested by Kaplan-Meier analyses in a prospectively collected TNBC cohort of 49 samples from the no-chemotherapy arms of IBCSG trials VIII and IX, and by logistic regression in a chemotherapy-treated cohort of 121 TNBCs from combined IBCSG trials and institutional repositories. High methylation was associated with shorter recurrence-free interval in the no-chemotherapy arm of the IBCSG studies, as well as in the chemotherapy-treated patients within the combined institutional and IBCSG chemotherapy cohorts (100 marker panel,  = 0.002; 30 marker panel,  = 0.05). Chromosome 19 sites were enriched among these loci. In conclusion, our hypermethylation signatures identify increased recurrence risk independent of whether patients receive chemotherapy.
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http://dx.doi.org/10.1038/s41523-020-0145-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994477PMC
January 2020

Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration.

PLoS Genet 2020 01 13;16(1):e1008588. Epub 2020 Jan 13.

Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, California, United States of America.

Prostate embryonic development, pubertal and adult growth, maintenance, and regeneration are regulated through androgen signaling-mediated mesenchymal-epithelial interactions. Specifically, the essential role of mesenchymal androgen signaling in the development of prostate epithelium has been observed for over 30 years. However, the identity of the mesenchymal cells responsible for this paracrine regulation and related mechanisms are still unknown. Here, we provide the first demonstration of an indispensable role of the androgen receptor (AR) in sonic hedgehog (SHH) responsive Gli1-expressing cells, in regulating prostate development, growth, and regeneration. Selective deletion of AR expression in Gli1-expressing cells during embryogenesis disrupts prostatic budding and impairs prostate development and formation. Tissue recombination assays showed that urogenital mesenchyme (UGM) containing AR-deficient mesenchymal Gli1-expressing cells combined with wildtype urogenital epithelium (UGE) failed to develop normal prostate tissue in the presence of androgens, revealing the decisive role of AR in mesenchymal SHH responsive cells in prostate development. Prepubescent deletion of AR expression in Gli1-expressing cells resulted in severe impairment of androgen-induced prostate growth and regeneration. RNA-sequencing analysis showed significant alterations in signaling pathways related to prostate development, stem cells, and organ morphogenesis in AR-deficient Gli1-expressing cells. Among these altered pathways, the transforming growth factor β1 (TGFβ1) pathway was up-regulated in AR-deficient Gli1-expressing cells. We further demonstrated the activation of TGFβ1 signaling in AR-deleted prostatic Gli1-expressing cells, which inhibits prostate epithelium growth through paracrine regulation. These data demonstrate a novel role of the AR in the Gli1-expressing cellular niche for regulating prostatic cell fate, morphogenesis, and renewal, and elucidate the mechanism by which mesenchymal androgen-signaling through SHH-responsive cells elicits the growth and regeneration of prostate epithelium.
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http://dx.doi.org/10.1371/journal.pgen.1008588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980684PMC
January 2020

Aberrant activation of hepatocyte growth factor/MET signaling promotes β-catenin-mediated prostatic tumorigenesis.

J Biol Chem 2020 01 9;295(2):631-644. Epub 2019 Dec 9.

Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California 91010-3000. Electronic address:

Co-occurrence of aberrant hepatocyte growth factor (HGF)/MET proto-oncogene receptor tyrosine kinase (MET) and Wnt/β-catenin signaling pathways has been observed in advanced and metastatic prostate cancers. This co-occurrence positively correlates with prostate cancer progression and castration-resistant prostate cancer development. However, the biological consequences of these abnormalities in these disease processes remain largely unknown. Here, we investigated the aberrant activation of HGF/MET and Wnt/β-catenin cascades in prostate tumorigenesis by using a newly generated mouse model in which both murine transgene and stabilized β-catenin are conditionally co-expressed in prostatic epithelial cells. These compound mice displayed accelerated prostate tumor formation and invasion compared with their littermates that expressed only stabilized β-catenin. RNA-Seq and quantitative RT-PCR analyses revealed increased expression of genes associated with tumor cell proliferation, progression, and metastasis. Moreover, Wnt signaling pathways were robustly enriched in prostate tumor samples from the compound mice. ChIP-qPCR experiments revealed increased β-catenin recruitment within the regulatory regions of the gene in tumor cells of the compound mice. Interestingly, the occupancy of MET on the promoter also appeared in the compound mouse tumor samples, implicating a novel role of MET in β-catenin-mediated transcription. Results from implanting prostate graft tissues derived from the compound mice and controls into HGF-transgenic mice further uncovered that HGF induces prostatic oncogenic transformation and cell growth. These results indicate a role of HGF/MET in β-catenin-mediated prostate cancer cell growth and progression and implicate a molecular mechanism whereby nuclear MET promotes aberrant Wnt/β-catenin signaling-mediated prostate tumorigenesis.
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http://dx.doi.org/10.1074/jbc.RA119.011137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956540PMC
January 2020

Borderline Estrogen Receptor-Positive Breast Cancers in Black and White Women.

J Natl Cancer Inst 2020 07;112(7):728-736

Department of Epidemiology, Gillings School of Global Public Health.

Background: Some breast tumors expressing greater than 1% and less than 10% estrogen receptor (ER) positivity (ER-borderline) are clinically aggressive; others exhibit luminal biology. Prior ER-borderline studies included few black participants.

Methods: Using the Carolina Breast Cancer Study (phase I: 1993-1996; 2: 1996-2001; 3: 2008-2013), a population-based study that oversampled black women, we compared ER-borderline (n = 217) to ER-positive (n = 1885) and ER-negative (n = 757) tumors. PAM50 subtype and risk of recurrence score (ROR-PT, incorporates subtype, proliferation, tumor size) were measured. Relative frequency differences (RFD) were estimated using multivariable linear regression. Disease-free interval (DFI) was evaluated by ER category and endocrine therapy receipt, overall and by race, using Kaplan Meier and Cox models. Statistical tests were two-sided.

Results: ER-borderlines were more frequently basal-like (RFD = +37.7%, 95% confidence interval [CI] = 27.1% to 48.4%) and high ROR-PT (RFD = +52.4%, 95% CI = 36.8% to 68.0%) relative to ER-positives. Having a high ROR-PT ER-borderline tumor was statistically significantly associated with black race (RFD = +26.2%, 95% CI = 9.0% to 43.3%). Compared to ER-positives, DFI of ER-borderlines treated with endocrine therapy was poorer but not statistically significantly different (hazard ratio [HR] = 2.03, 95% CI = 0.89% to 4.65%), whereas DFI was statistically significantly worse for ER-borderlines without endocrine therapy (HR = 3.33, 95% CI = 1.84% to 6.02%). However, black women with ER-borderline had worse DFI compared to ER-positives, even when treated with endocrine therapy (HR = 2.77, 95% CI = 1.09% to 7.04%).

Conclusions: ER-borderline tumors were genomically heterogeneous, with survival outcomes that differed by endocrine therapy receipt and race. Black race predicted high-risk ER-borderlines and may be associated with poorer endocrine therapy response.
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http://dx.doi.org/10.1093/jnci/djz206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357313PMC
July 2020

The comprehensive role of E-cadherin in maintaining prostatic epithelial integrity during oncogenic transformation and tumor progression.

PLoS Genet 2019 10 28;15(10):e1008451. Epub 2019 Oct 28.

Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.

E-cadherin complexes with the actin cytoskeleton via cytoplasmic catenins and maintains the functional characteristics and integrity of the epithelia in normal epithelial tissues. Lost expression of E-cadherin disrupts this complex resulting in loss of cell polarity, epithelial denudation and increased epithelial permeability in a variety of tissues. Decreased expression of E-cadherin has also been observed in invasive and metastatic human tumors. In this study, we investigated the effect of E-cadherin loss in prostatic epithelium using newly developed genetically engineered mouse models. Deletion of E-cadherin in prostatic luminal epithelial cells with modified probasin promoter driven Cre (PB-Cre4) induced the development of mouse prostatic intraepithelial neoplasia (PIN). An increase in levels of cytoplasmic and nuclear β-catenin appeared in E-cadherin deleted atypical cells within PIN lesions. Using various experimental approaches, we further demonstrated that the knockdown of E-cadherin expression elevated free cytoplasmic and nuclear β-catenin and enhanced androgen-induced transcription and cell growth. Intriguingly, pathological changes representing prostatic epithelial cell denudation and increased apoptosis accompanied the above PIN lesions. The essential role of E-cadherin in maintaining prostatic epithelial integrity and organization was further demonstrated using organoid culture approaches. To directly assess the role of loss of E-cadherin in prostate tumor progression, we generated a new mouse model with bigenic Cdh1 and Pten deletion in prostate epithelium. Early onset, aggressive tumor phenotypes presented in the compound mice. Strikingly, goblet cell metaplasia was observed, intermixed within prostatic tumor lesions of the compound mice. This study provides multiple lines of novel evidence demonstrating a comprehensive role of E-cadherin in maintaining epithelial integrity during the course of prostate oncogenic transformation, tumor initiation and progression.
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http://dx.doi.org/10.1371/journal.pgen.1008451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816545PMC
October 2019

Bimodal age distribution at diagnosis in breast cancer persists across molecular and genomic classifications.

Breast Cancer Res Treat 2020 Jan 18;179(1):185-195. Epub 2019 Sep 18.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Purpose: Female breast cancer demonstrates bimodal age frequency distribution patterns at diagnosis, interpretable as two main etiologic subtypes or groupings of tumors with shared risk factors. While RNA-based methods including PAM50 have identified well-established clinical subtypes, age distribution patterns at diagnosis as a proxy for etiologic subtype are not established for molecular and genomic tumor classifications.

Methods: We evaluated smoothed age frequency distributions at diagnosis for Carolina Breast Cancer Study cases within immunohistochemistry-based and RNA-based expression categories. Akaike information criterion (AIC) values compared the fit of single density versus two-component mixture models. Two-component mixture models estimated the proportion of early-onset and late-onset categories by immunohistochemistry-based ER (n = 2860), and by RNA-based ESR1 and PAM50 subtype (n = 1965). PAM50 findings were validated using pooled publicly available data (n = 8103).

Results: Breast cancers were best characterized by bimodal age distribution at diagnosis with incidence peaks near 45 and 65 years, regardless of molecular characteristics. However, proportional composition of early-onset and late-onset age distributions varied by molecular and genomic characteristics. Higher ER-protein and ESR1-RNA categories showed a greater proportion of late age-at-onset. Similarly, PAM50 subtypes showed a shifting age-at-onset distribution, with most pronounced early-onset and late-onset peaks found in Basal-like and Luminal A, respectively.

Conclusions: Bimodal age distribution at diagnosis was detected in the Carolina Breast Cancer Study, similar to national cancer registry data. Our data support two fundamental age-defined etiologic breast cancer subtypes that persist across molecular and genomic characteristics. Better criteria to distinguish etiologic subtypes could improve understanding of breast cancer etiology and contribute to prevention efforts.
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http://dx.doi.org/10.1007/s10549-019-05442-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985047PMC
January 2020

Mammographic density: intersection of advocacy, science, and clinical practice.

Curr Breast Cancer Rep 2019 09 24;11(3):100-110. Epub 2019 Jul 24.

Al Quds University, Jerusalem, West Bank.

Purpose: Here we aim to review the association between mammographic density, collagen structure and breast cancer risk.

Findings: While mammographic density is a strong predictor of breast cancer risk in populations, studies by Boyd show that mammographic density does not predict breast cancer risk in individuals. Mammographic density is affected by age, parity, menopausal status, race/ethnicity, and body mass index (BMI).New studies normalize mammographic density to BMI may provide a more accurate way to compare mammographic density in women of diverse race and ethnicity. Preclinical and tissue-based studies have investigated the role collagen composition and structure in predicting breast cancer risk. There is emerging evidence that collagen structure may activate signaling pathways associated with aggressive breast cancer biology.

Summary: Measurement of film mammographic density does not adequately capture the complex signaling that occurs in women with at-risk collagen. New ways to measure at-risk collagen potentially can provide a more accurate view of risk.
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http://dx.doi.org/10.1007/s12609-019-00316-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728377PMC
September 2019

Loss of the tumor suppressor, Tp53, enhances the androgen receptor-mediated oncogenic transformation and tumor development in the mouse prostate.

Oncogene 2019 09 29;38(38):6507-6520. Epub 2019 Jul 29.

Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA, 91010-3000, USA.

Recent genome analysis of human prostate cancers demonstrated that both AR gene amplification and TP53 mutation are among the most frequently observed alterations in advanced prostate cancer. However, the biological role of these dual genetic alterations in prostate tumorigenesis is largely unknown. In addition, there are no biologically relevant models that can be used to assess the molecular mechanisms for these genetic abnormalities. Here, we report a novel mouse model, in which elevated transgenic AR expression and Trp53 deletion occur simultaneously in mouse prostatic epithelium to mimic human prostate cancer cells. These compound mice developed an earlier onset of high-grade prostatic intraepithelial neoplasia and accelerated prostate tumors in comparison with mice harboring only the AR transgene. Histological analysis showed prostatic sarcomatoid and basaloid carcinomas with massive squamous differentiation in the above compound mice. RNA-sequencing analyses identified a robust enrichment of the signature genes for human prostatic basal cell carcinomas in the above prostate tumors. Master regulator analysis revealed SOX2 as a transcriptional regulator in prostatic basal cell tumors. Elevated expression of SOX2 and its downstream target genes were detected in prostatic tumors of the compound mice. Chromatin immunoprecipitation analyses implicate a coregulatory role of AR and SOX2 in the expression of prostatic basal cell signature genes. Our data demonstrate a critical role of SOX2 in prostate tumorigenesis and provide mechanistic insight into prostate tumor aggressiveness and progression mediated by aberrant AR and p53 signaling pathways.
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http://dx.doi.org/10.1038/s41388-019-0901-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752978PMC
September 2019

CaMKK2 in myeloid cells is a key regulator of the immune-suppressive microenvironment in breast cancer.

Nat Commun 2019 06 4;10(1):2450. Epub 2019 Jun 4.

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.

Tumor-associated myeloid cells regulate tumor growth and metastasis, and their accumulation is a negative prognostic factor for breast cancer. Here we find calcium/calmodulin-dependent kinase kinase (CaMKK2) to be highly expressed within intratumoral myeloid cells in mouse models of breast cancer, and demonstrate that its inhibition within myeloid cells suppresses tumor growth by increasing intratumoral accumulation of effector CD8 T cells and immune-stimulatory myeloid subsets. Tumor-associated macrophages (TAMs) isolated from Camkk2 mice expressed higher levels of chemokines involved in the recruitment of effector T cells compared to WT. Similarly, in vitro generated Camkk2 macrophages recruit more T cells, and have a reduced capability to suppress T cell proliferation, compared to WT. Treatment with CaMKK2 inhibitors blocks tumor growth in a CD8 T cell-dependent manner, and facilitates a favorable reprogramming of the immune cell microenvironment. These data, credential CaMKK2 as a myeloid-selective checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer.
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http://dx.doi.org/10.1038/s41467-019-10424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547743PMC
June 2019

Expression of tetraspanins NET-6 and CD151 in breast cancer as a potential tumor biomarker.

Clin Exp Med 2019 Aug 20;19(3):377-384. Epub 2019 Apr 20.

Department of Laboratory Medicine, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, Guangxi, China.

Tetraspanins have been implicated in multiple biological functions including protein networking and cell signaling. NET-6 (TSPAN 13) has been demonstrated to be a tumor suppressor gene in breast cancer, while CD151 is more likely to act as an oncogene. However, the biological function of both proteins is still inconclusive. Immunohistochemistry was used to analyze the expression of NET-6 and CD151 proteins in breast tumors and benign epithelial cells. The cellular expression of both markers was correlated with HER2, ER, and PR status as well as tumor grade, Ki-67 scores, invasion, and metastasis. Expression of NET-6 and CD151 was variable both in tumors and in benign epithelial cells. Expression of NET-6 and CD151 was stronger in tumors than in benign epithelial cells. The expression of NET-6 was also stronger in HER2-negative, low-grade, lymphovascular invasion-negative, and non-metastatic breast tumors. There was no correlation between NET-6 expression and ER, or PR, or triple-negative status. There was no correlation between CD151 expression and HER2, ER, PR, or triple-negative status, tumor grade, or Ki-67 scores, invasion, and metastasis. The expression of tetraspanins NET-6 and CD151 may indicate an alteration of their biological function during neoplastic transformation. NET-6 expression in tumors might be a potential marker indicating the outcome of breast cancer.
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http://dx.doi.org/10.1007/s10238-019-00554-xDOI Listing
August 2019

Deletion of the p16INK4a tumor suppressor and expression of the androgen receptor induce sarcomatoid carcinomas with signet ring cells in the mouse prostate.

PLoS One 2019 24;14(1):e0211153. Epub 2019 Jan 24.

Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.

The tumor suppressor p16Ink4a, encoded by the INK4a gene, is an inhibitor of cyclin D-dependent kinases 4 and 6, CDK4 and CDK6. This inhibition prevents the phosphorylation of the retinoblastoma protein (pRb), resulting in cellular senescence through inhibition of E2F-mediated transcription of S phase genes required for cell proliferation. The p16Ink4a plays an important role in tumor suppression, whereby its deletion, mutation, or epigenetic silencing is a frequently observed genetic alteration in prostate cancer. To assess its roles and related molecular mechanisms in prostate cancer initiation and progression, we generated a mouse model with conditional deletion of p16Ink4a in prostatic luminal epithelium. The mice underwent oncogenic transformation and developed prostatic intraepithelial neoplasia (PIN) from eight months of age, but failed to develop prostatic tumors. Given the prevalence of aberrant androgen signaling pathways in prostate cancer initiation and progression, we then generated R26hARL/wt:p16L/L: PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16Ink4a co-occur in prostatic luminal epithelial cells. While R26hARL/wt:PB-Cre4 mice showed no visible pathological changes, R26hARL/wt:p16L/L: PB-Cre4 compound mice displayed an early onset of high-grade PIN (HGPIN), prostatic carcinoma, and metastatic lesions. Strikingly, we observed tumors resembling human sarcomatoid carcinoma with intermixed focal regions of signet ring cell carcinoma (SRCC) in the prostates of the compound mice. Further characterization of these tumors showed they were of luminal epithelial cell origin, and featured characteristics of epithelial to mesenchymal transition (EMT) with enhanced proliferative and invasive capabilities. Our results not only implicate a biological role for AR expression and p16Ink4a deletion in the pathogenesis of prostatic SRCC, but also provide a new and unique genetically engineered mouse (GEM) model for investigating the molecular mechanisms for SRCC development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211153PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345450PMC
October 2019

Differences in race, molecular and tumor characteristics among women diagnosed with invasive ductal and lobular breast carcinomas.

Cancer Causes Control 2019 Jan 8;30(1):31-39. Epub 2019 Jan 8.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 135 Dauer Dr, Chapel Hill, NC, 27599, USA.

Background: The dominant invasive breast cancer histologic subtype, ductal carcinoma, shows intrinsic subtype diversity. However, lobular breast cancers are predominantly Luminal A. Both histologic subtypes show distinct relationships with patient and tumor characteristics, but it is unclear if these associations remain after accounting for intrinsic subtype.

Methods: Generalized linear models were used to estimate relative frequency differences (RFDs) and 95% confidence intervals (95% CIs) for the associations between age, race, tumor characteristics, immunohistochemistry (IHC) and RNA-based intrinsic subtype, TP53 status, and histologic subtype in the Carolina Breast Cancer Study (CBCS, n = 3,182) and The Cancer Genome Atlas (TCGA, n = 808).

Results: Relative to ductal tumors, lobular tumors were significantly more likely to be Luminal A [CBCS RNA RFD: 44.9%, 95% CI (39.6, 50.1); TCGA: RFD: 50.5%, 95% CI (43.9, 57.1)], were less frequent among young (≤ 50 years) and black women, were larger in size, low grade, less frequently had TP53 pathway defects, and were diagnosed at later stages. These associations persisted among Luminal A tumors (n = 242).

Conclusions: While histology is strongly associated with molecular characteristics, histologic associations with age, race, size, grade, and stage persisted after restricting to Luminal A subtype. Histology may continue to be clinically relevant among Luminal A breast cancers.
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http://dx.doi.org/10.1007/s10552-018-1121-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396692PMC
January 2019

Image analysis with deep learning to predict breast cancer grade, ER status, histologic subtype, and intrinsic subtype.

NPJ Breast Cancer 2018 3;4:30. Epub 2018 Sep 3.

1Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.

RNA-based, multi-gene molecular assays are available and widely used for patients with ER-positive/HER2-negative breast cancers. However, RNA-based genomic tests can be costly and are not available in many countries. Methods for inferring molecular subtype from histologic images may identify patients most likely to benefit from further genomic testing. To identify patients who could benefit from molecular testing based on H&E stained histologic images, we developed an image analysis approach using deep learning. A training set of 571 breast tumors was used to create image-based classifiers for tumor grade, ER status, PAM50 intrinsic subtype, histologic subtype, and risk of recurrence score (ROR-PT). The resulting classifiers were applied to an independent test set ( = 288), and accuracy, sensitivity, and specificity of each was assessed on the test set. Histologic image analysis with deep learning distinguished low-intermediate vs. high tumor grade (82% accuracy), ER status (84% accuracy), Basal-like vs. non-Basal-like (77% accuracy), Ductal vs. Lobular (94% accuracy), and high vs. low-medium ROR-PT score (75% accuracy). Sampling considerations in the training set minimized bias in the test set. Incorrect classification of ER status was significantly more common for Luminal B tumors. These data provide proof of principle that molecular marker status, including a critical clinical biomarker (i.e., ER status), can be predicted with accuracy >75% based on H&E features. Image-based methods could be promising for identifying patients with a greater need for further genomic testing, or in place of classically scored variables typically accomplished using human-based scoring.
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http://dx.doi.org/10.1038/s41523-018-0079-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120869PMC
September 2018

Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.

Clin Cancer Res 2018 12 6;24(23):5860-5872. Epub 2018 Aug 6.

University of Michigan Rogel Cancer Center and the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.

Purpose: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)-positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (). mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy.

Experimental Design: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common by droplet digital PCR (BioRad).

Results: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER, two of whom had CTC-ER reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC ( = 0.0003). Fourteen of 45 (31%) patients had ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline status was not prognostic. Patients with persistently elevated CTC and/or ctDNA at C1D15 had worse PFS than patients who did not ( = 0.0007).

Conclusions: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER and ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1569DOI Listing
December 2018

Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy.

Proc Natl Acad Sci U S A 2018 07 9;115(31):7869-7878. Epub 2018 Jul 9.

Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215;

Endocrine therapy resistance invariably develops in advanced estrogen receptor-positive (ER) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER breast cancer. At low CSK levels, as is the case in patients with ER breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER tumors.
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http://dx.doi.org/10.1073/pnas.1722617115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077722PMC
July 2018

TP53 protein levels, RNA-based pathway assessment, and race among invasive breast cancer cases.

NPJ Breast Cancer 2018 25;4:13. Epub 2018 Jun 25.

1Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.

Mutations in tumor suppressor have been inconsistently linked to breast cancer risk factors and survival. Immunohistochemistry (IHC) staining, a primary clinical means of mutation determination, only detects mutations that facilitate protein accumulation (e.g., missense mutations). RNA-based pathway methods capture functional status and may aid in understanding the role of TP53 function in racial disparities of breast cancer. status was assessed among invasive breast cancer cases from the Carolina Breast Cancer Study (CBCS) (2008-2013) using IHC and an established RNA-based TP53 signature (CBCS and The Cancer Genome Atlas (TCGA)). Frequency of TP53 status (IHC, RNA-based) was estimated in association with tumor characteristics, PAM50 intrinsic subtype, age, and race using relative frequency differences (RFDs) and 95% confidence intervals (95% CI) as the measure of association. Approximately 60% of basal-like tumors were TP53 protein positive (IHC), while nearly 100% were TP53 mutant-like (RNA). Luminal A tumors had low frequency of TP53 positivity (IHC: 7.9%) and mutant-like status (RNA: 1.7%). Mutant-like TP53 (RNA) was strongly associated with age ≤50 years, high tumor grade, advanced stage of disease, large tumor size, and basal-like and HER2 intrinsic subtypes. Black race was strongly associated with TP53 mutant-like status (RNA (RFD: 24.8%, 95% CI: 20.5, 29.0) even after adjusting for age, grade, stage (RFD: 11.3%; 95% CI: 7.6, 15.0). Associations were attenuated and non-significant when measured by IHC. IHC-based TP53 status is an insensitive measurement of TP53 functional status. RNA-based methods suggest a role for TP53 in tumor prognostic features and racial disparities.
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http://dx.doi.org/10.1038/s41523-018-0067-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018637PMC
June 2018

Differential cellular localization of CELSR2 and ING4 and correlations with hormone receptor status in breast cancer.

Histol Histopathol 2018 Aug 28;33(8):835-842. Epub 2018 Feb 28.

Institute of Laboratory Medicine, Guangdong Medical University, Dongguan, Guangdong, China.

CELSR2 is postulated to be a receptor involved in contact-mediated communication; however, its expression and function in cancer remain unknown. ING4 is a tumor suppresor encoded by the ING4 gene which inhibits cell growth. The expression of CELSR2 and ING4 in breast tumors and in benign epithelial cells have been analyzed and correlated with HER2, ER, and PR status. Immunohistochemistry was used to analyze the expression of CELSR2 and ING4 protein in breast tumors and benign epithelial cells. The differential cellular localization of both markers was analyzed and results were also correlated with HER2, ER, and PR status. CELSR2 and ING4 cytoplasmic expression was significantly stronger in tumors than in benign epithelial cells, while the nuclear expression of both markers was significantly stronger in benign epithelial cells than in tumors. When comparing the two markers in the same type of tissues, the nuclear expression of CELSR2 was significantly stronger than cytoplasmic in benign epithelial cells, while there was no significant difference in the cellular localization of CELSR2 in tumors. For ING4, the cytoplasmic expression was significantly stronger than nuclear expression in tumors, while in benign epithelial cells, ING4 was expressed at similar levels in both compartments. There was no correlation between CELSR2 expression and HER2, ER, and PR status in tumors. However, the cytoplasmic expression of ING4 was associated with HER2 positivity in tumors. Both CELSR2 and ING4 display increased cytoplasmic staining in breast cancer cells compared to benign epithelium, suggesting a possible role of both genes in the pathogenesis of human mammary neoplasia.
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http://dx.doi.org/10.14670/HH-11-979DOI Listing
August 2018

Frequency of breast cancer subtypes among African American women in the AMBER consortium.

Breast Cancer Res 2018 02 6;20(1):12. Epub 2018 Feb 6.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Breast cancer subtype can be classified using standard clinical markers (estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)), supplemented with additional markers. However, automated biomarker scoring and classification schemes have not been standardized. The aim of this study was to optimize tumor classification using automated methods in order to describe subtype frequency in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium.

Methods: Using immunohistochemistry (IHC), we quantified the expression of ER, PR, HER2, the proliferation marker Ki67, and two basal-like biomarkers, epidermal growth factor receptor (EGFR) and cytokeratin (CK)5/6, in 1381 invasive breast tumors from African American women. RNA-based (prediction analysis of microarray 50 (PAM50)) subtype, available for 574 (42%) cases, was used to optimize classification. Subtype frequency was calculated, and associations between subtype and tumor characteristics were estimated using logistic regression.

Results: Relative to ER, PR and HER2 from medical records, central IHC staining and the addition of Ki67 or combined tumor grade improved accuracy for classifying PAM50-based luminal subtypes. Few triple negative cases (< 2%) lacked EGFR and CK5/6 expression, thereby providing little improvement in accuracy for identifying basal-like tumors. Relative to luminal A subtype, all other subtypes had higher combined grade and were larger, and ER-/HER2+ tumors were more often lymph node positive and late stage tumors. The frequency of basal-like tumors was 31%, exceeded only slightly by luminal A tumors (37%).

Conclusions: Our findings indicate that automated IHC-based classification produces tumor subtype frequencies approximating those from PAM50-based classification and highlight high frequency of basal-like and low frequency of luminal A breast cancer in a large study of African American women.
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http://dx.doi.org/10.1186/s13058-018-0939-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801839PMC
February 2018

XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype.

Cancer Res 2018 04 19;78(7):1726-1738. Epub 2018 Jan 19.

Department of Surgery, Division of Surgical Sciences, Duke University Medical Center, Durham, North Carolina.

Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked EGFR (EGFR/HER2)-mediated MAPK signaling to NFκB hyperactivity, but the mechanism(s) by which this occurs remain unclear. Here, we report that the X-linked inhibitor of apoptosis protein (XIAP) plays a central role in linking these two pathways. XIAP overexpression correlated with poor prognoses in breast cancer patients and was frequently observed in untreated IBC patient primary tumors. XIAP drove constitutive NFκB transcriptional activity, which mediated ALDH positivity (a marker of stem-like cells), tumor growth, and an IBC expression signature in patient-derived IBC cells. Using pathway inhibitors and mathematical models, we defined a new role for the MAPK interacting (Ser/Thr)-kinase (MNK) in enhancing XIAP expression and downstream NFκB signaling. Furthermore, targeted XIAP knockdown and treatment with a MNK inhibitor decreased tumor cell migration in a dorsal skin fold window chamber murine model that allowed for intravital imaging of local tumor growth and migration. Together, our results indicate a novel role for XIAP in the molecular cross-talk between MAPK and NFκB pathways in aggressive tumor growth, which has the potential to be therapeutically exploited. Signaling by the MNK kinase is essential in inflammatory breast cancer, and it can be targeted to inhibit XIAP-NFκB signaling and the aggressive phenotype of this malignancy. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724565PMC
April 2018

Prediagnostic Smoking Is Associated with Binary and Quantitative Measures of ER Protein and mRNA Expression in Breast Tumors.

Cancer Epidemiol Biomarkers Prev 2018 01 13;27(1):67-74. Epub 2017 Nov 13.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina.

Smoking is a possible risk factor for breast cancer and has been linked to increased risk of estrogen receptor-positive (ER) disease in some epidemiologic studies. It is unknown whether smoking has quantitative effects on ER expression. We examined relationships between smoking and ER expression from tumors of 1,888 women diagnosed with invasive breast cancer from a population-based study in North Carolina. ER expression was characterized using binary (±) and continuous measures for ER protein, mRNA, and a multigene luminal score (LS) that serves as a measure of estrogen signaling in breast tumors. We used logistic and linear regression models to estimate temporal and dose-dependent associations between smoking and ER measures. The odds of ER, , and LS tumors among current smokers (at the time of diagnosis), those who smoked 20 or more years, and those who smoked within 5 years of diagnosis were nearly double those of nonsmokers. Quantitative levels of were highest among current smokers compared with never smokers overall [mean (log) = 9.2 vs. 8.7, < 0.05] and among ER cases; however, we did not observe associations between smoking measures and continuous ER protein expression. In relationship to breast cancer diagnosis, recent smoking was associated with higher odds of the ER, , and LS subtype. Current smoking was associated with elevated mRNA levels and an elevated LS, but not with altered ER protein. A multigene LS and single-gene mRNA may capture tumor changes associated with smoking. .
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http://dx.doi.org/10.1158/1055-9965.EPI-17-0404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760366PMC
January 2018

Reproductive risk factor associations with lobular and ductal carcinoma in the Carolina Breast Cancer Study.

Cancer Causes Control 2018 01 9;29(1):25-32. Epub 2017 Nov 9.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Background: Invasive lobular breast tumors display unique reproductive risk factor profiles. Lobular tumors are predominantly Luminal A subtype, and it is unclear whether reported risk factor associations are independent of molecular subtype.

Methods: Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the associations between risk factors and histologic subtype [ductal (n = 2,856), lobular (n = 326), and mixed ductal-lobular (n = 473)] in the Carolina Breast Cancer Study (1993-2013). Three-marker immunohistochemical clinical subtypes were defined as Luminal A (ER+ or PR+/HER2-), Luminal B (ER+ or PR+/HER2+), Triple Negative (ER-/PR-/HER2-), and HER2+ (ER-/PR-/HER2+).

Results: In case-case analyses compared to ductal, lobular tumors were significantly associated with lactation duration > 12 months [OR 1.86, 95% CI (1.33-2.60)], age at first birth ≥ 26 years [OR: 1.35, 95% CI: (1.03-1.78)], and current oral contraceptive use [OR: 1.86, 95% CI: (1.08-3.20)]. Differences in risk factor associations between ductal and lobular tumors persisted after restricting to Luminal A subtype.

Conclusions: Lobular tumors were associated with older age at first birth, increased lactation duration, and current oral contraceptive use. Etiologic heterogeneity by histology persisted after restricting to Luminal A subtype, suggesting both tumor histology and intrinsic subtype play integral parts in breast cancer risk.
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http://dx.doi.org/10.1007/s10552-017-0977-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903274PMC
January 2018

Ki-67 Expression in Breast Cancer Tissue Microarrays: Assessing Tumor Heterogeneity, Concordance With Full Section, and Scoring Methods.

Am J Clin Pathol 2017 Aug;148(2):108-118

Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY.

Objectives: Ki-67 has been proposed to be used as a surrogate marker to differentiate luminal breast carcinomas (BCs). The purpose of this study was to determine the utility of and best approaches for using tissue microarrays (TMAs) and Ki-67 staining to distinguish luminal subtypes in large epidemiology studies of luminal/human epidermal growth factor receptor 2 (HER2)-negative BC.

Methods: Full-section and TMA (three 0.6-mm cores and two 1.0-mm cores) slides of 109 cases were stained with Ki-67 antibody. We assessed two ways of collapsing TMA cores: a weighted approach and mitotically active approach.

Results: For cases with at least a single 0.6-mm TMA core (n = 107), 16% were misclassified using a mitotically active approach and 11% using a weighted approach. For cases with at least a single 1.0-mm TMA core (n = 101), 5% were misclassified using either approach. For the 0.6-mm core group, there were 33.3% discordant cases. The number of discordant cases increased from 18% in the group of two cores to 40% in the group of three cores (P = .039).

Conclusions: Ki-67 tumor heterogeneity was common in luminal/HER2- BC. Using a weighted approach was better than using a mitotically active approach for core to case collapsing. At least a single 1.0-mm core or three 0.6-mm cores are required when designing a study using TMA.
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http://dx.doi.org/10.1093/ajcp/aqx053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848430PMC
August 2017

Racial Differences in PAM50 Subtypes in the Carolina Breast Cancer Study.

J Natl Cancer Inst 2018 02;110(2)

Department of Epidemiology, Lineberger Comprehensive Cancer Center; Department of Pathology and Lab Medicine, Department of Nutrition (EHA), and Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC; Dana Farber Cancer Institute, Harvard University, Boston, MA; Center for Clinical Cancer Genetics, Global Health Department of Medicine, The University of Chicago, Chicago, IL.

Background: African American breast cancer patients have lower frequency of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative disease and higher subtype-specific mortality. Racial differences in molecular subtype within clinically defined subgroups are not well understood.

Methods: Using data and biospecimens from the population-based Carolina Breast Cancer Study (CBCS) Phase 3 (2008-2013), we classified 980 invasive breast cancers using RNA expression-based PAM50 subtype and recurrence (ROR) score that reflects proliferation and tumor size. Molecular subtypes (Luminal A, Luminal B, HER2-enriched, and Basal-like) and ROR scores (high vs low/medium) were compared by race (blacks vs whites) and age (≤50 years vs > 50 years) using chi-square tests and analysis of variance tests.

Results: Black women of all ages had a statistically significantly lower frequency of Luminal A breast cancer (25.4% and 33.6% in blacks vs 42.8% and 52.1% in whites; younger and older, respectively). All other subtype frequencies were higher in black women (case-only odds ratio [OR] = 3.11, 95% confidence interval [CI] = 2.22 to 4.37, for Basal-like; OR = 1.45, 95% CI = 1.02 to 2.06, for Luminal B; OR = 2.04, 95% CI = 1.33 to 3.13, for HER2-enriched). Among clinically HR+/HER2- cases, Luminal A subtype was less common and ROR scores were statistically significantly higher among black women.

Conclusions: Multigene assays highlight racial disparities in tumor subtype distribution that persist even in clinically defined subgroups. Differences in tumor biology (eg, HER2-enriched status) may be targetable to reduce disparities among clinically ER+/HER2- cases.
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http://dx.doi.org/10.1093/jnci/djx135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059138PMC
February 2018

Prostate-derived Ets factor, an oncogenic driver in breast cancer.

Tumour Biol 2017 May;39(5):1010428317691688

3 Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.

Prostate-derived Ets factor (PDEF), a member of the Ets family of transcription factors, differs from other family members in its restricted expression in normal tissues and its unique DNA-binding motif. These interesting attributes coupled with its aberrant expression in cancer have rendered PDEF a focus of increasing interest by tumor biologists. This review provides a current understanding of the characteristics of PDEF expression and its role in breast cancer. The bulk of the evidence is consistent with PDEF overexpression in most breast tumors and an oncogenic role for this transcription factor in breast cancer. In addition, high PDEF expression in estrogen receptor-positive breast tumors showed significant correlation with poor overall survival in several independent cohorts of breast cancer patients. Together, these findings demonstrate PDEF to be an oncogenic driver of breast cancer and a biomarker of poor prognosis in this cancer. Based on this understanding and the limited expression of PDEF in normal human tissues, the development of PDEF-based therapeutics for prevention and treatment of breast cancer is also discussed.
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http://dx.doi.org/10.1177/1010428317691688DOI Listing
May 2017
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