Publications by authors named "Asma Tulbah"

64 Publications

Clinical Identification of Dysregulated Circulating microRNAs and Their Implication in Drug Response in Triple Negative Breast Cancer (TNBC) by Target Gene Network and Meta-Analysis.

Genes (Basel) 2021 Apr 9;12(4). Epub 2021 Apr 9.

Breast Cancer Research, Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

Resistance to therapy is a persistent problem that leads to mortality in breast cancer, particularly triple-negative breast cancer (TNBC). MiRNAs have become a focus of investigation as tissue-specific regulators of gene networks related to drug resistance. Circulating miRNAs are readily accessible non-invasive potential biomarkers for TNBC diagnosis, prognosis, and drug-response. Our aim was to use systems biology, meta-analysis, and network approaches to delineate the drug resistance pathways and clinical outcomes associated with circulating miRNAs in TNBC patients. MiRNA expression analysis was used to investigate differentially regulated circulating miRNAs in TNBC patients, and integrated pathway regulation, gene ontology, and pharmacogenomic network analyses were used to identify target genes, miRNAs, and drug interaction networks. Herein, we identified significant differentially expressed circulating miRNAs in TNBC patients (miR-19a/b-3p, miR-25-3p, miR-22-3p, miR-210-3p, miR-93-5p, and miR-199a-3p) that regulate several molecular pathways (PAM (PI3K/Akt/mTOR), HIF-1, TNF, FoxO, Wnt, and JAK/STAT, PD-1/PD-L1 pathways and EGFR tyrosine kinase inhibitor resistance (TKIs)) involved in drug resistance. Through meta-analysis, we demonstrated an association of upregulated miR-93, miR-210, miR-19a, and miR-19b with poor overall survival outcomes in TNBC patients. These results identify miRNA-regulated mechanisms of drug resistance and potential targets for combination with chemotherapy to overcome drug resistance in TNBC. We demonstrate that integrated analysis of multi-dimensional data can unravel mechanisms of drug-resistance related to circulating miRNAs, particularly in TNBC. These circulating miRNAs may be useful as markers of drug response and resistance in the guidance of personalized medicine for TNBC.
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http://dx.doi.org/10.3390/genes12040549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068962PMC
April 2021

Carcinomas of the Uterine Cervix: Comprehensive Review With An Update on Pathogenesis, Nomenclature of Precursor and Invasive Lesions, and Differential Diagnostic Considerations.

Adv Anat Pathol 2021 May;28(3):150-170

Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, Qatar.

Most cervical carcinomas and their related lesions are attributed to an infection by human papillomavirus (HPV). The infection usually starts in the basal cells at the squamocolumnar junction. It causes cell proliferation and maturation abnormalities along with nuclear abnormalities resulting in low-grade squamous intraepithelial lesions. An overwhelming majority of these lesions spontaneously disappear, and the infection is cleared. In a small subset of high-risk HPV infection cases, the lesions may persist and progress to high-grade squamous intraepithelial lesions. These are associated with the incorporation of the viral genome into the human genome. Some of the high-grade squamous intraepithelial lesions, over several years, progress to invasive carcinoma. Carcinomas of the cervix are usually squamous cell carcinomas (SCCs), but 20% to 25% of the cases may manifest as adenocarcinomas. Similar to SCC, adenocarcinomas may initially manifest as adenocarcinomas in situ and may progress to invasive carcinomas after a variable period of time. In the recently published World Health Organization classification of female genital tumors, SCCs, and adenocarcinomas of the cervix are divided into HPV-associated and HPV-independent tumors. This review draws on the latest terminology and the several morphologic subtypes recognized for each category.
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http://dx.doi.org/10.1097/PAP.0000000000000300DOI Listing
May 2021

Impact of Pathologic Complete Response following Neoadjuvant Chemotherapy ± Trastuzumab in Locally Advanced Breast Cancer.

J Oncol 2021 12;2021:6639763. Epub 2021 Feb 12.

Medical Oncology Section, Oncology Centre, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11564, Saudi Arabia.

Purpose: This study was designed to examine the relationship between breast cancer molecular subtypes and pathological response to neoadjuvant chemotherapy (NAC) ± trastuzumab, in locally advanced breast cancer (LABC).

Methods: Female patients with LABC (T2-T4, N0-N2, and M0) who received neoadjuvant chemotherapy + trastuzumab if HER2+ subtype, followed by surgery and radiotherapy ± hormonal therapy, were identified. The primary endpoint was pathologic complete response (pCR) in the breast and axilla (ypT0/ypN0), with final analysis on disease-free survival (DFS) and overall survival (OS).

Results: Six hundred eighty-one patients with a median age of 44 years, premenopausal: 70%, median tumour size: 7.0 cm (range 4-11 cm), stage II B: 27% and III A/III B: 73%, ER+/HER2-: 40.8%, ER-/HER2-: 23%, ER+/HER2+: 17.7%, and ER-/HER2+: 18.5%. Overall pCR (ypT0/ypN0) was 23%. The pCR rates based on molecular subtypes were ER+/HER2-: 9%; ER+/HER2+: 29%; ER-/HER2-: 31%; and ER-/HER2+: 37%. At median follow-up of 61 months, ER+/HER2+ and ER+/HER2- subtypes had the best 5-year DFS and OS; meanwhile, ER-/HER2+ and ER-/HER2- subtypes had the worst.

Conclusion: Women with ER+/HER2- disease are the least likely to achieve pCR, with the highest rates in HER2+ and triple-negative subgroups. Degree of response is associated with OS; despite the comparatively higher likelihood of achieving pCR in ER-/HER2+ and triple-negative, these subgroups experience a survival detriment. We are consistent with the published data that patients who attain the pathological complete response defined as ypT0/ypN0 have improved outcomes.
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http://dx.doi.org/10.1155/2021/6639763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895557PMC
February 2021

Differential expression of PD-L1 between primary and metastatic epithelial ovarian cancer and its clinico-pathological correlation.

Sci Rep 2021 Feb 12;11(1):3750. Epub 2021 Feb 12.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, MBC#98-16, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.

Ovarian cancer (OC) is one of the most common gynecologic cancer, which has the worst prognosis and highest mortality rate. The lack of curative treatment and the high relapse rate, especially in advanced OC, continues to present a clinical challenge, highlighting the need for new therapeutic strategies. This study was performed to compare the expression of PD-L1 in primary epithelial ovarian cancer (EOC) and their corresponding peritoneal metastases, as well as to evaluate its correlation with clinico-pathological parameters. In total, 194 treatment naïve paired EOC and peritoneal metastasis were analyzed by immunohistochemistry for PD-L1 expression. Clinico-pathological information was available for all patients. Significant differences in PD-L1 expression were found between primary EOC and peritoneal metastasis (p < 0.0001). We found discordant tumor cell PD-L1 expression between primary tumors and corresponding peritoneal metastasis in 34% (66/194) of cases. Furthermore, PD-L1 expression in peritoneal metastasis samples was significantly associated with adverse prognostic factors, such as high proliferative index (Ki67) (p = 0.0039) and high histologic grade (p = 0.0330). In conclusion, the discordance of PD-L1 expression between primary EOC and corresponding peritoneal metastases suggests that its assessment as a potential biomarker for predicting response to anti-PD-L1 therapy may require analysis of metastatic lesions.
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http://dx.doi.org/10.1038/s41598-021-83276-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881132PMC
February 2021

Single-Institute Review of HER-2/Neu-Positive Invasive Lobular Breast Carcinoma in an Arab Population.

Am J Case Rep 2021 Feb 5;22:e928012. Epub 2021 Feb 5.

Section Medical Oncology, Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

BACKGROUND Invasive lobular carcinoma is special subtype of breast cancer that has clinical behavior and morphology distinct from other breast cancer subtypes. It accounts for 5-15% of breast cancer. Overall, HER-2 gene amplification occurs at a significantly lower rate in ILC, but also has been linked to adverse outcomes. Most cases of ILCs with HER-2 overexpression and or amplification generally have the pleomorphic variant. We report the first series of cases from Saudi Arabia for this rare cancer in an Arab population. CASE REPORT Nine patients retrospectively were evaluated with HER-2/neu-positive ILC of the breast that were diagnosed and managed from 2003 to 2020. Four patients were diagnosed as early breast cancer, 3 had metastatic disease and 2 were locally advanced at their initial presentation. The mean age was 58 years; 30% were classic ILC and another 60% were of mixed non-classic variants (histologic pattern represented by nuclear pleomorphism). Management of patients with HER-2-positive ILC was performed according to standard multimodality breast cancer guidelines, consisting of surgery, chemotherapy with anti-HER-2/neu blockade, radiation, and endocrine therapy, based on stage and hormone status. CONCLUSIONS In conclusion, HER-2-positive invasive lobular carcinoma of the breast is uncommon in the Arab population, which has not been previously reported in the literature. Further studies are warranted to explore the biology, molecular characteristics, and clinical course in this group of patients.
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http://dx.doi.org/10.12659/AJCR.928012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872945PMC
February 2021

PD-L1 Protein Expression in Middle Eastern Breast Cancer Predicts Favorable Outcome in Triple-Negative Breast Cancer.

Cells 2021 Jan 25;10(2). Epub 2021 Jan 25.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia.

Programmed cell-death ligand 1 (PD-L1) has been shown to induce potent T-cell mediated anti-tumoral immunity. The significance of PD-L1 expression in the prognosis of breast cancer (BC) remains controversial and its prevalence and prognostic value in breast cancer from Middle Eastern ethnicity is lacking. A total of 1003 unselected Middle Eastern breast cancers were analyzed for PD-L1 expression using immunohistochemistry. PD-L1 expression, seen in 32.8% (329/1003) of cases, was significantly associated with poor prognostic indicators such as younger patients, high-grade tumors, estrogen-receptor (ER)-negative, progesterone-receptor (PR)-negative, and triple-negative breast cancers (TNBC) as well as high Ki-67 index. We also found a significant association between PD-L1 expression and deficient mismatch repair protein expression. No association was found between PD-L1 expression and clinical outcome. However, on further subgroup analysis, PD-L1 expression was found to be an independent marker for favorable overall survival and recurrence-free survival in TNBC. In conclusion, we demonstrated strong association between PD-L1 and mismatch repair deficiency in Middle Eastern BC patients and that PD-L1 overexpression in tumor cells was an independent prognostic marker in TNBCs from Middle Eastern ethnicity. Overall, these findings might help in the development of more appropriate treatment strategies for BC in Middle Eastern population.
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http://dx.doi.org/10.3390/cells10020229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910988PMC
January 2021

Clinical and functional significance of tumor/stromal ATR expression in breast cancer patients.

Breast Cancer Res 2020 05 15;22(1):49. Epub 2020 May 15.

Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, MBC#03, Riyadh, 11211, Saudi Arabia.

Background: Most breast cancer-associated fibroblasts (CAFs) are active and important cancer-promoting cells, with significant impact on patient prognosis. Therefore, we investigated here the role of the protein kinase ATR in breast stromal fibroblasts in the prognosis of locally advanced breast cancer patients.

Methods: We have used immunohistochemistry to assess the level of ATR in breast cancer tissues and their adjacent normal tissues. Immunoblotting as well as quantitative RT-PCR were utilized to show the role of breast cancer cells and IL-6 as well as AUF-1 in downregulating ATR in breast stromal fibroblasts. Engineered human breast tissue model was also used to show that ATR-deficient breast stromal fibroblasts enhance the growth of breast cancer cells.

Results: We have shown that the protein kinase ATR is downregulated in cancer cells and their neighboring CAFs in breast cancer tissues as compared to their respective adjacent normal tissues. The implication of cancer cells in ATR knockdown in CAFs has been proven in vitro by showing that breast cancer cells downregulate ATR in breast fibroblasts in an IL-6/STAT3-dependent manner and via AUF-1. In another cohort of 103 tumors from locally advanced breast cancer patients, we have shown that absence or reduced ATR expression in tumoral cells and their adjacent stromal fibroblasts is correlated with poor overall survival as well as disease-free survival. Furthermore, ATR expression in CAFs was inversely correlated with tumor recurrence and progression.

Conclusion: ATR downregulation in breast CAFs is frequent, procarcinogenic, and correlated with poor patient survival.
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http://dx.doi.org/10.1186/s13058-020-01289-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229635PMC
May 2020

Genetic heterogeneity and evolutionary history of high-grade ovarian carcinoma and matched distant metastases.

Br J Cancer 2020 04 26;122(8):1219-1230. Epub 2020 Feb 26.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.

Background: High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian carcinoma, associated with poor clinical outcome and metastatic disease. Although metastatic processes are becoming more understandable, the genomic landscape and metastatic progression in HGSOC has not been elucidated.

Methods: Multi-region whole-exome sequencing was performed on HGSOC primary tumours and their metastases (n = 33 tumour regions) from six patients. The resulting somatic variants were analysed to delineate tumour evolution and metastatic dissemination, and to compare the repertoire of events between primary HGSOC and metastasis.

Results: All cases presented branching evolution patterns in primary HGSOC, with three cases further showing parallel evolution in which different mutations on separate branches of a phylogenetic tree converge on the same gene. Furthermore, linear metastatic progression was observed in 67% of cases with late dissemination, in which the metastatic tumour mostly acquires the same mutational process active in primary tumour, and parallel metastatic progression, with early dissemination in the remaining 33.3% of cases. Metastatic-specific SNVs were further confirmed as late dissemination events. We also found the involvement of metastatic-specific driver events in the Wnt/β-catenin pathway, and identified potential clinically actionable events in individual patients of the metastatic HGSOC cohort.

Conclusions: This study provides deeper insights into clonal evolution and mutational processes that can pave the way to new therapeutic targets.
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http://dx.doi.org/10.1038/s41416-020-0763-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156387PMC
April 2020

Complete Response of Chemo-Refractory Metastatic Metaplastic Breast Cancer to Paclitaxel-Immunotherapy Combination.

Am J Case Rep 2019 Nov 6;20:1630-1635. Epub 2019 Nov 6.

Stem Cell and Tissue Re-Engineering Program, Research Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

BACKGROUND Metaplastic breast cancer (MPBC) is a rare subtype of breast cancer that is difficult to manage and is resistant to therapy. Immunotherapy is becoming a promising option for care of several types of cancers including triple negative breast cancer. CASE REPORT We present a case of a patient with chemo-refractory metastatic metaplastic-type of breast cancer with failures to 3 active lines of chemotherapy. The patient achieved a complete and sustained response to chemo-immunotherapy combination with acceptable tolerability and minimal adverse events. The treatment was a combination of anti-PD-L1 antibody (durvalumab) immunotherapy in combination with the chemotherapeutic agent, paclitaxel. CONCLUSIONS This is the first case reporting the successful use of durvalumab and paclitaxel combination for treatment of triple negative breast cancer in general, and in metastatic MPBC in specific.
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http://dx.doi.org/10.12659/AJCR.918770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858626PMC
November 2019

Telomerase reverse transcriptase promoter mutations in cancers derived from multiple organ sites among middle eastern population.

Genomics 2020 03 31;112(2):1746-1753. Epub 2019 Oct 31.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia. Electronic address:

Sanger Sequencing and immunohistochemistry was employed to investigate the TERT promoter mutations and TERT protein expression with their association to clinicopathological characteristics in over 2200 samples of Middle Eastern origin from 13 different types of cancers. The TERT promoter mutations were most frequently present in bladder cancer (68.6%), followed by central nervous system tumors (28.7%), thyroid cancer (15.4%), prostate cancer (9.3%), endometrial carcinoma (3.7%), rhabdomyosarcoma (1.4%), colorectal cancer (1%), epithelial ovarian carcinoma (0.7%) and breast cancer (0.7%). No mutations were observed in other types of cancers. In bladder cancer, we found significant inverse association with metastasis and a trend to good survival in patients with TERT mutations. In gliomas, TERT promoter mutations predicted poor prognosis. In thyroid cancer, high frequency of TERT mutation was observed in poorly differentiated carcinoma. In addition, TERT promoter mutations were associated with aggressive markers and poor outcome in follicular thyroid carcinomas.
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http://dx.doi.org/10.1016/j.ygeno.2019.09.017DOI Listing
March 2020

Prevalence of Human Papillomavirus (HPV) Infection and the Association with Survival in Saudi Patients with Head and Neck Squamous Cell Carcinoma.

Cancers (Basel) 2019 Jun 13;11(6). Epub 2019 Jun 13.

Department of Pathology & Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

Head and neck squamous cell carcinoma (HNSCC) shows wide disparities, association with human papillomavirus (HPV) infection, and prognosis. We aimed at determining HPV prevalence, and its prognostic association with overall survival (OS) in Saudi HNSCC patients. The study included 285 oropharyngeal and oral-cavity HNSCC patients. HPV was detected using HPV Linear-Array and RealLine HPV-HCR. In addition, p16INK4a (p16) protein overexpression was evaluated in 50 representative cases. Oropharyngeal cancers were infrequent (10%) compared to oral-cavity cancers (90%) with no gender differences. Overall, HPV-DNA was positive in 10 HNSCC cases (3.5%), mostly oropharyngeal (21%). However, p16 expression was positive in 21 cases of the 50 studied (42%) and showed significantly higher OS ( = 0.02). Kaplan-Meier univariate analysis showed significant associations between patients' OS and age ( < 0.001), smoking ( = 0.02), and tumor stage ( < 0.001). A Cox proportional hazard multivariate analysis confirmed the significant associations with age, tumor stage, and also treatment ( < 0.01). In conclusion, HPV-DNA prevalence was significantly lower in our HNSCC patients than worldwide 32-36% estimates ( ≤ 0.001). Although infrequent, oropharyngeal cancer increased over years and showed 21% HPV-DNA positivity, which is close to the worldwide 36-46% estimates ( = 0.16). Besides age, smoking, tumor stage, and treatment, HPV/p16 status was an important determinant of patients' survival. The HPV and/or p16 positivity patients had a better OS than HPV/p16 double-negative patients ( = 0.05). Thus, HPV/p16 status helps improve prognosis by distinguishing between the more favorable p16/HPV positive and the less favorable double-negative tumors.
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http://dx.doi.org/10.3390/cancers11060820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627701PMC
June 2019

Prevalence, spectrum, and founder effect of BRCA1 and BRCA2 mutations in epithelial ovarian cancer from the Middle East.

Hum Mutat 2019 06 18;40(6):729-733. Epub 2019 Mar 18.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Germline mutations in breast cancer susceptibility gene 1 and 2 have previously been estimated to contribute to 13-18% of all epithelial ovarian cancer (EOC). To characterize the prevalence and effect of BRCA1 and BRCA2 mutations in Middle Eastern EOC patients, BRCA mutation screening was performed in 407 unselected ovarian cancer patients using targeted capture and/or Sanger sequencing. A total of 19 different pathogenic variants (PVs) were identified in 50 (12.3%) women. Nine PVs were recurrent accounting for 80% of cases with PVs (40/50) in the entire cohort. Founder mutation analysis revealed only two mutations (c.4136_4137delCT and c.1140dupG) sharing the same haplotypes thus representing founder mutations in the Middle Eastern population. Identification of the mutation spectrum, prevalence, and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment, and development of a cost-effective screening strategy.
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http://dx.doi.org/10.1002/humu.23736DOI Listing
June 2019

β1 Integrin is essential for fascin-mediated breast cancer stem cell function and disease progression.

Int J Cancer 2019 08 18;145(3):830-841. Epub 2019 Feb 18.

Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Breast cancer remains the second cause of tumor-related mortality in women worldwide mainly due to chemoresistance and metastasis. The chemoresistance and metastasis are attributed to a rare subpopulation with enriched stem-like characteristics, thus called Cancer Stem Cells (CSCs). We have previously reported aberrant expression of the actin-bundling protein (fascin) in breast cancer cells, which enhances their chemoresistance, metastasis and enriches CSC population. The intracellular mechanisms that link fascin with its downstream effectors are not fully elucidated. Here, loss and gain of function approaches in two different breast cancer models were used to understand how fascin promotes disease progression. Importantly, findings were aligned with expression data from actual breast cancer patients. Expression profiling of a large breast cancer dataset (TCGA, 530 patients) showed statistically significant correlation between fascin expression and a key adherence molecule, β1 integrin (ITGB1). In vitro manipulation of fascin expression in breast cancer cells exhibited its direct effect on ITGB1 expression. Fascin-mediated regulation of ITGB1 was critical for several breast cancer cell functions including adhesion to different extracellular matrix, self-renewability and chemoresistance. Importantly, there was a significant relationship between fascin and ITGB1 co-expression and short disease-free as well as overall survival in chemo-treated breast cancer patients. This novel role of fascin effect on ITGB1 expression and its outcome on cell self-renewability and chemoresistance strongly encourages for dual targeting of fascin-ITGB1 axis as a therapeutic approach to halt breast cancer progression and eradicate it from the root.
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http://dx.doi.org/10.1002/ijc.32183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593770PMC
August 2019

Overexpression of PARP is an independent prognostic marker for poor survival in Middle Eastern breast cancer and its inhibition can be enhanced with embelin co-treatment.

Oncotarget 2018 Dec 18;9(99):37319-37332. Epub 2018 Dec 18.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Patients with aggressive breast cancer (BC) subtypes usually don't have favorable prognosis despite the improvement in treatment modalities. These cancers still remain a major cause of morbidity and mortality in females. This has fostered a major effort to discover actionable molecular targets to treat these patients. Poly ADP ribose polymerase (PARP) is one of these molecular targets that are under comprehensive investigation for treatment of such tumors. However, its role in the pathogenesis of BC from Middle Eastern ethnicity has not yet been explored. Therefore, we examined the expression of PARP protein in a large cohort of over 1000 Middle Eastern BC cases by immunohistochemistry. Correlation with clinico-pathological parameters were performed. Nuclear PARP overexpression was observed in 44.7% of all BC cases and was significantly associated with aggressive clinico-pathological markers. Interestingly, nuclear PARP overexpression was an independent predictor of poor prognosis. PARP overexpression was also directly associated with XIAP overexpression, with PARP and XIAP co-expression in 15.8% (159/1008) of our cases. We showed that combined inhibition of PARP by olaparib and XIAP by embelin significantly and synergistically inhibited cell growth and induced apoptosis in BC cell lines. Finally, co-treatment of olaparib and embelin regressed BC xenograft tumor growth in nude mice. Our results revealed the role of PARP in Middle Eastern BC pathogenesis and prognosis. Furthermore, our data support the potential clinical development of combined inhibition of PARP and XIAP, which eventually could extend the utility of olaparib beyond BRCA deficient cancer.
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http://dx.doi.org/10.18632/oncotarget.26470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324669PMC
December 2018

Interleukin-8 Activates Breast Cancer-Associated Adipocytes and Promotes Their Angiogenesis- and Tumorigenesis-Promoting Effects.

Mol Cell Biol 2019 01 3;39(2). Epub 2019 Jan 3.

Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia

Increasing evidence supports the critical role of active stromal adipocytes in breast cancer development and spread. However, the mediators and the mechanisms of action are still elusive. We show here that cancer-associated adipocytes (CAAs) isolated from 10 invasive breast carcinomas are proinflammatory and exhibit active phenotypes, including higher proliferative, invasive, and migratory capacities compared to their adjacent tumor-counterpart adipocytes (TCAs). Furthermore, all CAAs secreted higher level of interleukin-8 (IL-8), which is critical in mediating the paracrine procarcinogenic effects of these cells. Importantly, ectopic expression of IL-8 in TCA cells activated them and enhanced their procarcinogenic effects both , in a STAT3-dependent manner, and In contrast, inhibition of the IL-8 signaling using specific short hairpin RNA, anti-IL-8 antibody, or reparixin suppressed the active features of CAAs, including their non-cell-autonomous tumor-promoting activities both on breast luminal cells and in orthotopic tumor xenografts in mice. IL-8 played also an important role in enhancing the proangiogenic effects of breast adipocytes. These results provide clear indication that IL-8 plays key roles in the activation of breast CAAs and acts as a major mediator for their paracrine protumorigenic effects. Thus, targeting CAAs by inhibiting the IL-8 pathway could have great therapeutic value.
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http://dx.doi.org/10.1128/MCB.00332-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321878PMC
January 2019

FoxM1 is an independent poor prognostic marker and therapeutic target for advanced Middle Eastern breast cancer.

Oncotarget 2018 Apr 3;9(25):17466-17482. Epub 2018 Apr 3.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Breast cancer (BC) is the most common cause of cancer-related death in females in Saudi Arabia. BC in Saudi women tend to behave more aggressively than breast cancer in the West. Therefore, identification of new molecular targets and treatment strategies are highly warranted to improve patient outcome. FoxM1 has been shown to play a critical role in pathogenesis of various malignancies. In this study, we explored the prevalence and clinical implication of FoxM1 overexpression in Saudi breast cancer. FoxM1 protein overexpression was seen in 79% (770/975) of BC tissues and was associated with aggressive clinical parameters such as younger age (< 30 yrs) ( = 0.0172), high grade ( < 0.0001), mucinous histology ( < 0.0001) and triple negative phenotype ( < 0.0001). Overexpression of FoxM1 was significantly associated with activated AKT ( < 0.0001), Ki67 expression ( < 0.0001), VEGF ( < 0.0001), MMP-9 ( < 0.0001), XIAP ( < 0.0001) and Bcl-xL ( = 0.0300). Importantly, FoxM1 overexpression is found to be an independent prognostic marker in multivariate analysis in advanced stage (Stage III and IV) breast cancer ( = 0.0298). data using BC cell lines showed that down-regulation of FoxM1 using specific inhibitor, thiostrepton or siRNA inhibited cell migration, invasion and angiogenesis. In addition, treatment of BC cell lines with thiostrepton resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. , thiostrepton treatment regressed MDA-MB-231 cells generated xenografts via down-regulation of FoxM1 and its downstream targets. Our results suggest that FoxM1 may be a potential therapeutic target for the treatment of aggressive breast cancers.
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http://dx.doi.org/10.18632/oncotarget.24739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915129PMC
April 2018

FoxM1 and β-catenin predicts aggressiveness in Middle Eastern ovarian cancer and their co-targeting impairs the growth of ovarian cancer cells.

Oncotarget 2018 Jan 16;9(3):3590-3604. Epub 2017 Dec 16.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Epithelial ovarian cancer (EOC) is a highly lethal disease with poor prognosis especially in advanced stage tumor. Emerging evidence has reported that aberrant upregulation of FoxM1 and β-catenin are closely associated with aggressiveness of human cancer. However, interplay between these factors in the aggressiveness of EOC is not fully illustrated. In this study, we show that FoxM1 is frequently increased in Middle Eastern EOC and associated with high proliferative index ( = 0.0007) and high grade tumor ( = 0.0024). Interestingly, FoxM1 is significantly associated with elevated nuclear β-catenin and the concomitant increase of FoxM1 and β-catenin is associated with advanced stage of EOC by immunohistochemical analysis of 261 samples of Saudi patients with EOC. Functional analysis showed that β-catenin is a direct transcriptional target of FoxM1 in EOC cell lines. FoxM1 inhibition either by specific inhibitor, thiostrepton or siRNA suppressed β-catenin expression, whereas overexpression of FoxM1 increased nuclear β-catenin expression. We identified two FoxM1 binding sites in the β-catenin promoter that specifically bound to FoxM1 protein. Down-regulation of FoxM1 using thiostrepton induced apoptosis and inhibited cell migration/invasion in EOC cells. Moreover, co-inhibition of FoxM1 by thiostrepton and β-catenin by FH535 significantly and synergistically inhibited EOC cell growth and . Collectively, our findings confer that co-targeting FoxM1/β-catenin signaling cascade may be a promising molecular therapeutic choice in advanced EOC.
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http://dx.doi.org/10.18632/oncotarget.23338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790485PMC
January 2018

The DNA methyl-transferase protein DNMT1 enhances tumor-promoting properties of breast stromal fibroblasts.

Oncotarget 2018 Jan 18;9(2):2329-2343. Epub 2017 Dec 18.

Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, KSA.

The activation of breast stromal fibroblasts is a crucial step toward tumor growth and spread. Therefore, it is extremely important to understand the molecular basis of this activation and determine the molecules and the mechanisms responsible for its sustainability. In the present report we have shown that the DNA methyl-transferase protein DNMT1 is critical for the activation of breast stromal fibroblasts as well as the persistence of their active status. Indeed, we have first revealed DNMT1 up-regulation in most cancer-associated fibroblasts relative to their corresponding adjacent normal fibroblasts. This effect resulted from HuR-dependent stabilization of the mRNA. Furthermore, ectopic expression of DNMT1 activated primary normal breast fibroblasts and promoted their pro-carcinogenic effects, both and in orthotopic tumor xenografts. By contrast, specific DNMT1 knockdown normalized breast myofibroblasts and repressed their cancer-promoting properties. These effects were sustained through inhibition of the IL-6/STAT3/NF-κB epigenetic cancer/inflammation positive feedback loop. Furthermore, we have shown that DNMT1-related activation of breast fibroblasts is mediated through upregulation of the RNA binding protein AUF1, which is also part of the loop. The present data demonstrate the critical function of DNMT1 in breast cancer-related sustained activation of breast stromal fibroblasts.
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http://dx.doi.org/10.18632/oncotarget.23411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788643PMC
January 2018

Expanding the spectrum of germline variants in cancer.

Hum Genet 2017 11 3;136(11-12):1431-1444. Epub 2017 Oct 3.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Our ability to identify germline variants in hereditary cancer cases remains challenged by the incomplete cataloging of relevant genes and lack of consensus on who should be tested. We designed a panel [hereditary oncogenesis predisposition evaluation (HOPE)] that encompasses most of the genes known to be associated with cancer development and tested its yield on more than 1300 samples of cancer patients. Pathogenic or likely pathogenic variants in high and intermediate risk genes were identified in 16, 23.9, 9.7 and 2.7%, respectively, of peripheral blood or normal tissue samples taken from patients with breast, ovarian, colorectal and thyroid cancer. To confirm specificity of these findings, we tested an ethnically matched cohort of 816 individuals and only identified pathogenic or likely pathogenic variants in 1.59% (0.98% in high risk and 0.61% in intermediate risk). Remarkably, pathogenic or likely pathogenic alleles in DNA repair/genomic instability genes (other than BRCA2, ATM and PALB2) accounted for at least 16.8, 11.1, 50 and 45.5% of mutation-positive breast, ovarian, thyroid and colorectal cancer patients, respectively. Family history was noticeably lacking in a substantial fraction of mutation-positive cases (63.7, 81.5, 42.4 and 87.5% in breast, ovarian, colorectal and thyroid, respectively). Our results show high contribution of germline mutations to cancer predisposition that extends beyond "classical" hereditary cancer genes. Family history was lacking in 63.5% mutation-positive cases, shows that hereditary cancer need not appear familial and suggests that relaxed selection of cancer patients for hereditary cancer panels should be considered.
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http://dx.doi.org/10.1007/s00439-017-1845-0DOI Listing
November 2017

Obesity and p16 Downregulation Activate Breast Adipocytes and Promote Their Protumorigenicity.

Mol Cell Biol 2017 Sep 11;37(17). Epub 2017 Aug 11.

Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia

Obesity is increasingly recognized as a risk factor for breast cancer development. However, the molecular basis of obesity-related breast carcinogenesis remains elusive. In this study, we have shown that obesity reduces the level of the tumor suppressor p16 protein in breast adipocytes, which showed active features and strong procarcinogenic potential both and in orthotopic tumor xenografts compared to mature adipocytes from lean women. Furthermore, obesity triggered epithelial-to-mesenchymal transition (EMT) in breast ductal epithelial cells. Interestingly, specific downregulation of p16 increased the expression/secretion levels of various adipokines, including leptin, and activated breast adipocytes from lean women. Consequently, like breast adipocytes from obese women, p16-deficient adipocytes induced EMT in normal primary breast luminal cells in a leptin-dependent manner and enhanced tumor growth. Additionally, we have shown that p16 negatively controls leptin at the mRNA level through microRNAs 141 and 146b-5p (miR-141 and miR-146b-5p), which bind the leptin mRNA at a specific sequence in the 3' untranslated region (UTR). These results show that obesity activates breast stromal adipocytes through p16 downregulation, which upregulates leptin and promotes procarcinogenic processes.
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http://dx.doi.org/10.1128/MCB.00101-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559683PMC
September 2017

Reply to "letter to the editor concerning the article-Impact of surgery on survival in stage IV breast cancer".

Breast J 2017 11 8;23(6):775. Epub 2017 May 8.

Department of Medical Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1111/tbj.12826DOI Listing
November 2017

Reduced rate of human papillomavirus infection and genetic overtransmission of TP53 72C polymorphic variant lower cervical cancer incidence.

Cancer 2017 Jul 10;123(13):2459-2466. Epub 2017 Apr 10.

Pathology & Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.

Background: Cervical cancer is a predominantly human papillomavirus (HPV)-driven disease worldwide. However, its incidence is unexplainably low in western Asia, including Saudi Arabia. Using this paradigm, we investigated the role of HPV infection rate and host genetic predisposition in TP53 G72C single nucleotide polymorphism (SNP) presumed to affect cancer incidence.

Methods: Patients treated between 1990 and 2012 were reviewed, and a series of 232 invasive cervical cancer cases were studied and compared with 313 matched controls without cancer. SNP was genotyped by way of direct sequencing. HPV linear array analysis was used to detect and genotype HPV in tumor samples.

Results: The incidence of cervical cancer revealed bimodal peaks at 42.5 years, with a slighter rebound at 60.8 years. Among all cases, 77% were HPV-positive and 16 HPV genotypes were detected-mostly genotypes 16 (75%) and 18 (9%)-with no difference by age, histology, or geographical region. Although the TP53 G72C genotype was not associated with overall cervical cancer risk, it was significantly associated with HPV positivity (odds ratio, 0.57; 95% confidence interval, 0.36-0.90; P = .016). Furthermore, the variant C allele was significantly overtransmitted in the population (P < .0003).

Conclusion: Cervical cancer incidence displays bimodal curve peaking at a young age with secondary rebound at older age. The combination of relative low HPV infection and variant TP53 72C allele overtransmission provide a plausible explanation for the low incidence of cervical cancer in our population. Therefore, HPV screening and host SNP genotyping may provide more relevant biomarkers to gauge the risk of developing cervical cancer. Cancer 2017;123:2459-66. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485004PMC
July 2017

Synovial sarcoma of the hard palate: The third case in the medical literature.

Hematol Oncol Stem Cell Ther 2019 Mar 1;12(1):60-63. Epub 2017 Feb 1.

Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Synovial sarcoma is a high-grade soft tissue sarcoma that rarely arises in the head and neck region. It affects the parapharyngeal space and the hypopharynx most commonly and it has different presentations based on the affected site. In extremely rare occasions, it involves the hard palate such as in our case where a 24-year-old female patient presented with a mass lesion involving the left hard palate, which was identified clinically and by imaging studies. The histopathological assessment confirmed that it was a monophasic synovial sarcoma which was also confirmed with further molecular studies. The patient underwent surgical excision and postoperative radiotherapy. Her close follow up over a 6-year period that followed her curative treatment has demonstrated no evidence of disease recurrence or distant metastasis. Surgical excision is the mainstay of treatment for synovial sarcoma and adjuvant radiotherapy is advised. Long-term follow up is recommended because of the remote possibility of late recurrence of the tumor.
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http://dx.doi.org/10.1016/j.hemonc.2016.12.005DOI Listing
March 2019

Reply to "Letter to the Editor Concerning the Article-Impact of Surgery on Survival in Stage IV Breast Cancer".

Breast J 2017 01 31;23(1):119. Epub 2016 Oct 31.

Department of Medical Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1111/tbj.12701DOI Listing
January 2017

Impact of Surgery on Survival in Stage IV Breast Cancer.

Breast J 2016 Nov 26;22(6):678-682. Epub 2016 Aug 26.

Department of Medical Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

We aimed to assess retrospectively the survival outcome in patients with stage IV breast cancer who underwent surgery. In a retrospective, nonrandomized study of stage IV breast cancer patients diagnosed in a single institution between 2000 and 2012, we assessed patient's survival in the context of baseline characteristics. A total 678 patients with metastatic breast cancer were included; 412 (60.77%) underwent surgery for the primary tumor (Surgery group), and 266 (39%) did not underwent surgery for the primary tumor (Nonsurgery group), with a median follow-up of 41 months. Patients in the Surgery group had longer survival (41 versus 27 months, p < 0.0029). The 5-year survival rate for Surgery group was 34% compared with 14% for the Nonsurgery group. A multivariate analysis revealed surgery (p = 0.0003), large tumor size (p = 0.0195), ER-positive (p < 0.0001), and metastasis at presentation (p = 0.0032) were prognostic variables. Loco-regional surgery does confer a survival advantage in stage IV breast cancer, however, selection bias cannot be excluded, a well-designed and powerful randomized, controlled trial would be valuable to answer whether surgery can improve survival.
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http://dx.doi.org/10.1111/tbj.12662DOI Listing
November 2016

Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis.

Int J Cancer 2016 09 3;139(5):1091-7. Epub 2016 May 3.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost-effective screening strategy.
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http://dx.doi.org/10.1002/ijc.30143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111783PMC
September 2016

Sentinel lymph node biopsy in clinically detected ductal carcinoma in situ.

World J Clin Oncol 2016 Apr;7(2):258-64

Ahmed Yahia Al-Ameer, Department of Surgery, Armed Forces Hospital Southern Region, Khamis Mushyt 61961, Kingdom of Saudi Arabia.

Aim: To study the indications for sentinel lymph node biopsy (SLNB) in clinically-detected ductal carcinoma in situ (CD-DCIS).

Methods: A retrospective analysis of 20 patients with an initial diagnosis of pure DCIS by an image-guided core needle biopsy (CNB) between June 2006 and June 2012 was conducted at King Faisal Specialist Hospital. The accuracy of performing SLNB in CD-DCIS, the rate of sentinel and non-sentinel nodal metastasis, and the histologic underestimation rate of invasive cancer at initial diagnosis were analyzed. The inclusion criteria were a preoperative diagnosis of pure DCIS with no evidence of invasion. We excluded any patient with evidence of microinvasion or invasion. There were two cases of mammographically detected DCIS and 18 cases of CD-DCIS. All our patients were diagnosed by an image-guided CNB except two patients who were diagnosed by fine needle aspiration (FNA). All patients underwent breast surgery, SLNB, and axillary lymph node dissection (ALND) if the SLN was positive.

Results: Twenty patients with an initial diagnosis of pure DCIS underwent SLNB, 2 of whom had an ALND. The mean age of the patients was 49.7 years (range, 35-70). Twelve patients (60%) were premenopausal and 8 (40%) were postmenopausal. CNB was the diagnostic procedure for 18 patients, and 2 who were diagnosed by FNA were excluded from the calculation of the underestimation rate. Two out of 20 had a positive SLNB and underwent an ALND and neither had additional non sentinel lymph node metastasis. Both the sentinel visualization rate and the intraoperative sentinel identification rate were 100%. The false negative rate was 0%. Only 2 patients had a positive SLNB (10%) and neither had additional metastasis following an ALND. After definitive surgery, 3 patients were upstaged to invasive ductal carcinoma (3/18 = 16.6%) and 3 other patients were upstaged to DCIS with microinvasion (3/18 = 16.6%). Therefore the histologic underestimation rate of invasive disease was 33%.

Conclusion: SLNB in CD-DCIS is technically feasible and highly accurate. We recommend limiting SLNB to patients undergoing a mastectomy.
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http://dx.doi.org/10.5306/wjco.v7.i2.258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826972PMC
April 2016

ALK alteration is a frequent event in aggressive breast cancers.

Breast Cancer Res 2015 Sep 17;17:127. Epub 2015 Sep 17.

Department of Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia.

Introduction: Breast cancer is the most common female malignancy worldwide and, despite improvements in treatment modalities, there are increased chances of recurrence and metastasis in a substantial number of cases and it remains one of the major causes of mortality among female cancer patients. Anaplastic lymphoma kinase (ALK) gene has been found to be altered in several solid and hematologic tumors. We aimed to comprehensively study the prevalence of ALK expression, and changes in copy number and translocation in a large cohort of breast cancer cases in a Middle Eastern population.

Methods: ALK protein expression was investigated by immunohistochemistry and numerical and structural variations of the ALK gene were analyzed by fluorescence in situ hybridization (FISH) in a tissue microarray format in a cohort of more than 1000 Middle Eastern breast cancers. The data were correlated with clinicopathologic parameters and other important molecular biomarkers.

Results: Immunohistochemical analysis showed ALK overexpression in 36.0 % of the breast cancer patients and gene amplification was present in 13.3 % of cases, seen by FISH analyses. ALK overexpression was significantly associated with ALK gene amplification (p = 0.0031). ALK-overexpressing tumors showed significant association with high-grade tumors (p = 0.0039), ductal histologic subtype (p = 0.0076), triple-negative phenotype (p = 0.0034), and high Ki-67 (p = 0.0001) and p-AKT (p <0.0001).

Conclusions: Immunohistochemical analysis showed ALK is overexpressed in a substantial proportion of breast cancers and possibly plays a significant role in the aggressive behavior of this cancer. Gene amplification is hypothesized to be a possible cause for a significant proportion of this overexpression. Based on these findings, a potential role for an ALK inhibitor, as a therapeutic agent targeting aggressive subtypes of breast cancer, merits further investigation.
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http://dx.doi.org/10.1186/s13058-015-0610-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588266PMC
September 2015

Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells.

Mol Cancer 2015 Aug 7;14:149. Epub 2015 Aug 7.

Stem Cell & Tissue Re-engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Background: The T-cell inhibitory molecule PD-L1 (B7-H1, CD274) is expressed on tumor cells of a subset of breast cancer patients. However, the mechanism that regulates PD-L1 expression in this group of patients is still not well-identified.

Methods: We have used loss and gain of function gene manipulation approach, multi-parametric flow cytometry, large scale gene expression dataset analysis and immunohistochemistry of breast cancer tissue sections.

Results: Induction of epithelial to mesenchymal transition (EMT) in human mammary epithelial cells upregulated PD-L1 expression, which was dependent mainly on the activation of the PI3K/AKT pathway. Interestingly, gene expression signatures available from large cohort of breast tumors showed a significant correlation between EMT score and the PD-L1 mRNA level (p < 0.001). Strikingly, very strong association (p < 0.0001) was found between PD-L1 expression and claudin-low subset of breast cancer, which is known to have high EMT score. On the protein level, significant correlation was found between PD-L1 expression and standard markers of EMT (p = 0.005) in 67 breast cancer patients. Importantly, specific downregulation of PD-L1 in claudin-low breast cancer cells showed signs of EMT reversal as manifested by CD44 and Vimentin downregulation and CD24 upregulation.

Conclusions: We have demonstrated a bidirectional effect between EMT status and PD-L1 expression especially in claudin-low subtype of breast cancer cells. Our findings highlights the potential dual benefit of anti-PD-L1 particularly in this subset of breast cancer patients that will likely benefit more from anti-PD-L1 targeted therapy as well as in monitoring biological changes upon treatment.
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http://dx.doi.org/10.1186/s12943-015-0421-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527106PMC
August 2015

Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer.

Breast Cancer Res Treat 2015 Jun 16;151(3):541-53. Epub 2015 May 16.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, MBC#98-16, P.O. Box 3354, Riyadh, 11211, Saudi Arabia,

PTEN is a tumor suppressor that negatively regulates the PI3 K-AKT signaling pathway which is involved in the pathogenesis of many different tumor types and serves as a prognostic marker in breast cancer. However, the significance of the role of PTEN in Middle Eastern ethnic breast cancer has not been explored especially with the fact that breast cancer originating from this ethnic population tend to behave more aggressively than breast cancer in the west. In this study, we analyzed PTEN alteration in a tissue microarray format containing more than 1000 primary breast cancers with clinical follow-up data. Tissue Microarray sections were analyzed for protein expression and copy number change using immunohistochemistry and fluorescence in situ hybridization. Loss of PTEN immunostaining was observed in 77 % of the cases. PTEN loss was significantly associated with large tumor size (p = 0.0030), high grade (p = 0.0281), tumor recurrence (p = 0.0333), and triple-negative breast cancers (p = 0.0086). PTEN loss in triple-negative breast cancers was significantly associated with rapid tumor cell proliferation (p = 0.0396) and poor prognosis (p = 0.0408). PTEN deletion was found only in 60 cases (6.4 %). Loss of PTEN protein expression occurs at high frequency in Middle Eastern breast cancer. PTEN inactivation may potentially lead to an aggressive behavior of tumor cells through stimulation of tumor cell proliferation. Furthermore, PTEN signaling pathway might be used as potential therapeutic target in triple-negative breast cancers since loss of its expression is shown to be significantly associated with this aggressive subtype of breast cancer.
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http://dx.doi.org/10.1007/s10549-015-3430-3DOI Listing
June 2015