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Androgen Receptor Expression and its Correlation with Other Risk Factors in Triple Negative Breast Cancers: a Report from Western Iran. Payandeh Mehrdad,Shazad Babak,Madani SeyedHamid,Ramezani Mazaher,Sadeghi Masoud Asian Pacific journal of cancer prevention : APJCP BACKGROUND:Androgen receptors (ARs) are expressed in more than 70% of breast cancers (BCs) and have been implicated in BC pathogenesis. Some triple negative (TN)BC tumors express AR and may benefit from ARtargeted therapies. The aim of this study was to evaluate survival and the prevalence of AR expression and its correlation with other risk factors in triple negative BCs in women from Western Iran. MATERIALS AND METHODS:In a retrospective study between 20092015, 41 patients with TNBC were referred to the Private Clinic of Oncology, Kermanshah city, Iran. ER, PR and ARpositive expression was defined as ≥10% nuclear staining and also HER2 (2+), FISH was performed. Nuclear staining was considered representative for Ki67 and P53. The mean followup for the patients was 25 months. In this time, 5 patients died and 4 lost to followup were censored from survival analysis. RESULTS:The mean age at diagnosis was 46.9 years (range, 2471 years) and all patients were female. The OS rates for ARpositive and ARnegative patients were 90% and 85.1%, respectively, and the mean OS was 26.3 and 23.2 months. Therefore, there was no significant difference between the two groups (Hazard ratio: 0.580, 95% CI: 0.0863.893, P=0.575). CONCLUSIONS:In TNBC patients, evaluation of AR status may provide additional information on prognosis and treatment. The results of studies showed that the prevalence AR expression may differ in the world and probably ethnicity can be an influencing factor.
The expression of programmed death-ligand 1 in patients with invasive breast cancer. Meng Yi,Wu Hongyan,Yao Yongzhong,Li Rong Gland surgery Background:The purpose of this study is to investigate the association between protein expression of programmed death-ligand 1 (PD-L1) and the clinicopathological features of patients with invasive breast cancer. Methods:Clinicopathological data of 651 patients with invasive breast carcinoma were collected over a 1-year period. Patients whose breast tissue samples did not express genes for the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor-2 (HER2) were classified as triple-negative breast cancer (TNBC). The correlations of PD-L1 expression with clinicopathological features and overall survival were determined using Pearson's correlation coefficient and logistic binary regression analysis, respectively. Results:Positive expression of PD-L1 was detected in 47% of patients with invasive breast carcinoma, compared with 69.3% of TNBC patients (P<0.05). Furthermore, expression of PD-L1 in patients with invasive breast carcinoma was significantly correlated with WHO grade, tumor size, vascular invasion, pathological stage, and the expression of ER, PR, nuclear associated antigen Ki67 (Ki67), gene, cytokeratin 5/6 (CK5/6), and epidermal growth factor receptor (EGFR) (P<0.05). Logistic binary regression analysis showed that WHO grade, Ki67, p53, and EGFR were independent risk factors for the expression of PD-L1 in patients with invasive breast cancer. Moreover, PD-L1 expression in TNBC patients was significantly correlated with WHO grade, neuro-invasion, Ki67, CK5/6, and EGFR (P<0.05), but it was not correlated with age, tumor size, vascular invasion, number of lymph nodes, pathological stage, or the expression of ER, PR, p53, androgen receptor (AR), or vascular endothelial growth factor receptor (VEGFR) (P>0.05). Conclusions:The high expression rate of PD-L1 in invasive breast cancer is closely related to some clinicopathological features. Thus, immunotherapy with PD-L1 inhibitors could be a potential treatment strategy for patients with invasive breast cancer. 10.21037/gs-20-824
Expression of ARs in triple negative breast cancer tumors: a potential prognostic factor? Giannos Aris,Filipits Martin,Zagouri Flora,Brandstetter Anita,Tsigginou Alexandra,Sotiropoulou Maria,Papaspyrou Irene,Sergentanis Theodoros N,Psaltopoulou Theodora,Rodolakis Alexandros,Antsaklis Aris,Dimopoulos Meletios-Athanasios,Dimitrakakis Constantine OncoTargets and therapy BACKGROUND/AIM:In light of the controversial published literature, this study aims to examine the potential prognostic role of AR immunohistochemical expression in triple negative breast cancer (TNBC). PATIENTS AND METHODS:Ninety patients with TNBC were included in this study; the associations between AR expression (Allred score), clinicopathological variables (stage, grade, histological subtype, tumor size, nodal status, age at diagnosis, Ki67 expression, and p53 expression), and overall survival were evaluated. RESULTS:AR expression was not associated with stage, grade, histological subtype, tumor size, nodal status, age at diagnosis, Ki67 expression, and p53 expression. AR immunopositivity was not associated with overall survival either at the univariate or at the multivariate Cox regression analysis (multivariate hazard ratio =0.66, 95% confidence interval: 0.26-1.70, P=0.393). CONCLUSION:AR expression does not seem to play a prognostic role in TNBC. 10.2147/OTT.S78254
Predictive Biomarker Profiling of > 6000 Breast Cancer Patients Shows Heterogeneity in TNBC, With Treatment Implications. Millis Sherri Z,Gatalica Zoran,Winkler Josiah,Vranic Semir,Kimbrough Jeffery,Reddy Sandeep,O'Shaughnessy Joyce A Clinical breast cancer BACKGROUND:Triple-negative breast cancer (TNBC) is an aggressive disease without established targeted treatment options for patients with metastatic disease. This study was undertaken to evaluate potentially actionable biomarkers in a large cohort of TNBC and compare them with non-TNBCs. MATERIALS AND METHODS:We evaluated 6341 (2111 TNBC and 4230 non-TNBC) breast cancer samples at a central laboratory for biomarkers of potential drug response across multiple platforms, including gene sequencing, protein expression, and gene copy number. RESULTS:TNBC expresses androgen receptor (AR) in a significantly (P < .05) lower percentage of cases (17%) than hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive breast carcinomas (59% and 79%, respectively), and gene comutations were differentially associated with AR-positive versus AR-negative cases. Higher AR expression levels in TNBC predicted for lower Ki-67 levels. Seventy percent of TNBC harbored a phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), v-akt murine thymoma viral oncogene homolog 1 (AKT1), or phosophatase and tensin homolog (PTEN) aberration. TNBC patients had a significantly lower PIK3CA mutation rate (13%) than all other subtypes (P < .05) and a higher tumor protein p53 (TP53) mutation rate (64%) than the estrogen receptor (ER)-positive cases (approximately 30%; P < .05). Topoisomerase 2 (TOP2A) amplification was observed in 1.3% of TNBC and in 1.6% of HER2-negative, HR-positive cancers; in contrast, HER2-positive, HR-negative or HR-positive cancers exhibited TOP2A amplification in 19% and 40% of cases, respectively (P <.05). CONCLUSION:Multi-platform molecular profiling identifies subgroups of TNBC with different biomarker profiles, suggesting numerous potentially targetable alterations in TNBC. TNBC is further characterized by different gene mutations and proliferative activity relative to AR expression, highlighting a need for comprehensive pathologic examination with potential to develop different, individualized treatment options. 10.1016/j.clbc.2015.04.008
Immunohistochemical co-expression status of cytokeratin 5/6, androgen receptor, and p53 as prognostic factors of adjuvant chemotherapy for triple negative breast cancer. Maeda Tetsuyo,Nakanishi Yoko,Hirotani Yukari,Fuchinoue Fumi,Enomoto Katsuhisa,Sakurai Kenichi,Amano Sadao,Nemoto Norimichi Medical molecular morphology Triple negative breast cancer (TNBC) is immunohistochemically characterised by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2). TNBC is known for its poor prognosis and high recurrence probability. There is no effective targeted treatment for TNBC, but only adjuvant chemotherapies. There are two TNBC subtypes, basal-like and non-basal-like, which are defined based on positive cytokeratin (CK) 5/6 and/or epidermal growth factor receptor (EGFR) expression. In particular, CK5/6 expression is reported to correlate with TNBC recurrence. TNBC lacks ER-α expression, but some TNBCs are known to express the androgen receptor (AR). Moreover, although p53 accumulation is detected in various malignant tumors, its influence on adjuvant chemotherapy for patients with TNBC remains unclear. The aim of this study was to assess the combined immunohistochemical expression of CK 5/6, AR, and p53 as a potential prognostic marker of adjuvant chemotherapy for patients with TNBC. The expression of CK5/6, AR, and p53 in formalin-fixed and paraffin-embedded (FFPE) surgical sections from 52 patients with TNBC was analysed by immunohistochemistry (IHC) and the co-expression patterns in individual cells were investigated by immunofluorescent (IF) staining. Low AR expression was correlated with high clinical stage (P < 0.05) and low nuclear grade (P < 0.05). The expression of CK5/6 and p53 did not correlate with clinicopathological features. Patients who needed adjuvant chemotherapy presented the worst prognosis. In particular, when the IHC expression pattern was CK5/6 (-), AR (-), and p53 (+), the disease free survival (DFS) and overall survival (OS) were the worst. On the other hand, patients with AR (+) and p53 (-) TNBC presented a good prognosis. The analysis of the co-expression status of these three markers showed that no cells presented both AR and CK5/6 expression. Furthermore, TP53 mRNA expression was higher in patients with AR-negative TNBC (P < 0.05) and in patients with the worst prognosis (P < 0.05) than in the other patients. These results suggested that, in patients with CK5/6-negative TNBC, AR expression correlated with good prognosis, but p53 accumulation correlated with poor prognosis. The present IHC markers allowed us to predict the post-surgery prognosis of patients with TNBC. In conclusion, TNBCs are heterogeneous. Patients with the CK5/6 (-), AR (-), and p53 (+) TNBC subtype, evaluated by IHC, presented the worst prognosis. These IHC markers will be helpful to follow patients with TNBC. 10.1007/s00795-015-0109-0
The Expression and Prognostic Significance of Claudin-8 and Androgen Receptor in Breast Cancer. OncoTargets and therapy PURPOSE:Claudin-8 (CLDN8) has been identified as an androgen-regulated gene in prostate cancer. However, the role of CLDN8 has not been fully explored in breast cancer. We aimed to explore the expression of CLDN8 and androgen receptor (AR), determine the correlation between CLDN8 and AR, assess the prognostic value of CLDN8 and AR co-expression, and investigate the possible CLDN8 expression molecular mechanism in breast cancer. MATERIALS AND METHODS:Twenty-eight pairs of fresh tumor tissues and adjacent noncancerous tissues were evaluated by Western blot for CLDN8. Then, 142 breast cancer samples were determined by immunohistochemistry for CLDN8 and AR. The association of clinicopathological features with CLDN8, AR and CLDN8, and AR co-expression was examined. The Cancer Genome Atlas (TCGA) was used to demonstrate the expression of CLDN8 and correlation between CLDN8 and AR. Kaplan-Meier survival analysis was performed to assess the prognostic impact of CLDN8 and AR co-expression. The mechanisms related to CLDN8 expression in breast cancer were explored by Gene Set Enrichment Analysis (GSEA). RESULTS:CLDN8 was downregulated in breast cancer tissues and positively correlated with none lymph node metastasis (=0.016), low histological grade (=0.006), positive ER (=0.014), positive PR (=0.003), low Ki-67 index (=0.017) and molecular subtypes (=0.012). CLDN8 level was significantly associated with AR level (r=0.348; <0.001). CLDN8 and AR co-expression was positively correlated with none lymph node metastasis (=0.007), low histological grade (=0.017), positive ER (=0.019), positive PR (=0.015) and low Ki-67 index group (=0.038). CLDN8 and AR co-expression had a better clinical prognosis. CONCLUSION:The expression of CLDN8 is directly related to the expression of AR. CLDN8 and AR co-expression might be a potential prognostic evaluation factor for breast cancer patients. 10.2147/OTT.S242406
Immunohistochemical Expression of Androgen Receptors (AR) in Various Breast Cancer Subtypes. Ismael Nour El Hoda S,Khairy Rasha A,Talaat Suzan M,El-Fattah Fatima A Abd Open access Macedonian journal of medical sciences BACKGROUND:Breast carcinoma ranks the first among malignant tumours in females and is the chief cause of cancer-related mortality. Androgen in implicated in the induction of proliferation and growth of mammary cells through binding to their corresponding receptors. Androgens influence the risk of acquiring breast cancer through either direct binding to androgen receptors (AR) or indirectly through their transformation to estradiol or competing for steroid binding proteins. AIM:To study the expression of AR in various breast cancer subtypes and to elucidate its clinical significance by correlating it with clinicopathological parameters. METHODS:One hundred and fifty breast cancer cases were studied using AR immunohistochemistry, and its expression was correlated with different clinicopathologic parameters and with ER, PR, Her-2/neu and Ki 67 expression. RESULTS:AR was expressed in 91 breast carcinoma cases out of 150 examined. There was a statistically significant correlation between AR expression and tumour size, mitotic count, tumour necrosis, infiltrative borders, the hormonal status of the tumour and subsequently luminal subtypes (p < 0.05). A subset of studied TNBC (34.6%) also expressed AR. On the other hand, there was no significant correlation between AR expression and other clinicopathological parameters. CONCLUSION:Positive AR immunostaining was associated with favourable prognostic factors and luminal subtypes (A&B). Also, a subset of TNBC cases showed positive AR expression. These results introduce the current potent, next-generation AR- antagonist as possible target therapy in breast cancer. Further researches on AR expression in breast cancer are recommended on a larger scale with follow up and survival to validate the current results. 10.3889/oamjms.2019.311
Association between tumor size and immunohistochemical expression of Ki-67, p53 and BCL2 in a node-negative breast cancer population selected from a breast cancer screening program. González-Sistal Angel,Sánchez Alicia Baltasar,Del Rio Ma Carmen,Arias José Ignacio,Herranz Michel,Ruibal Alvaro Anticancer research BACKGROUND/AIM:Breast cancer is the most common type of cancer among women. Breast infiltrating ductal carcinoma (IDC) is the most common type of breast cancer, approximately 80% of all breast carcinomas. The aim of this study was to analyze the association of tumor size, evaluated after histopathological analysis, with different clinical and biological parameters in IDC. MATERIALS AND METHODS:The study group included 251 women with IDC without axillary lymph node involvement, aged between 27 and 81 years. Analyzed parameters were: age, histological grade, menopausal status, menarche, pregnancy, abortion, breastfeeding, contraceptive use, hormone replacement therapy, estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), Ki-67, p53 and BCL2. RESULTS:Pathological tumor size was between 0.2 and 5.1 cm (1.43±0.86 cm). Tumors in 45 cases exceeded 2 cm, in eight 3 cm and only in one 5 cm. Pathological size was significantly associated with age >70 vs. <50 years (p=0.054), histological grade III vs. I (p=0.0003), positivity for Ki-67 (p=0.0003) and for p53 (p=0.0032). CONCLUSION:Tumor size was significantly associated with age >70 years, histological grade 3 and immunohistochemically-augmented expression of Ki-67 and p53.
Correction: Androgen Receptor (AR), E-Cadherin, and Ki-67 as Emerging Targets and Novel Prognostic Markers in Triple-Negative Breast Cancer (TNBC) Patients. Ricciardi Giuseppina Rosaria Rita,Adamo Barbara,Ieni Antonio,Licata Luana,Cardia Roberta,Ferraro Giuseppa,Franchina Tindara,Tuccari Giovanni,Adamo Vincenzo PloS one 10.1371/journal.pone.0132647
Insights for the application of TILs and AR in the treatment of TNBC in routine clinical practice. Losurdo Agnese,De Sanctis Rita,Fernandes Bethania,Torrisi Rosalba,Masci Giovanna,Agostinetto Elisa,Gatzemeier Wolfgang,Errico Valentina,Testori Alberto,Tinterri Corrado,Roncalli Massimo,Santoro Armando Scientific reports Triple negative breast cancer (TNBC), usually presenting with a very aggressive phenotype, is a heterogeneous entity. We aim to discuss new biomarkers, suitable for prognostic and predictive purposes. We retrospectively collected clinical variables and immunohistochemical characteristics of early TNBCs, specifically focusing on the prognostic and predictive significance of tumor infiltrating lymphocytes (TILs) and androgen receptor (AR) expression, assessing their correlation with clinical variables. Among 159 patients, TILs were significantly higher in younger patients and with lower BMI, and in tumors with higher ki-67 and greater nodal involvement; conversely, AR was significantly higher in older patients and in tumors with lower ki-67. Interestingly and in line with literature, both TILs level and ARs expression were lower within metastatic sites, in patients who developed distant metastases, compared to those found in the primary site. Small (pT1) and node negative tumors were highly represented and no correlation of either TILs or AR with prognosis could be observed. Our findings support the use of stromal TILs to identify a more aggressive, but chemo-sensitive phenotype, mostly represented in younger women, while AR may identify a less aggressive, slow-growing luminal TNBC subtype, more common among older patients. TILs and AR are worth implementing in routine clinical practice to refine prognosis even if, in our case series, we couldn't identify a significant correlation of the two variables with either disease-free and overall survival. 10.1038/s41598-020-77043-9
Claudin 4 expression in triple-negative breast cancer: correlation with androgen receptors and Ki-67 expression. Abd-Elazeem Mona A,Abd-Elazeem Marwa A Annals of diagnostic pathology Breast cancer is the most common malignancy in women and the leading cause of cancer mortality worldwide. Triple-negative breast cancer (TNBC) is an important phenotype of breast cancer that accounts for a relatively small number of breast cancer cases but still represent a focus of increasing interest at the clinical, biological, and epidemiological level. Claudins are the major component of the tight junction, and only a few studies have addressed the role of claudins in breast cancer, especially TNBC. Androgen receptors (ARs), as members of the nuclear receptor superfamily, are known to be involved in a complex network of signaling pathways that collectively regulate cell proliferation. However, roles of AR in breast cancer development and progression have not been very clearly understood. The proliferation marker Ki-67 has been confirmed as an independent predictive and prognostic factor in early breast cancer. The aims of this study are to identify the clinicopathologic associations and prognostic value of claudin 4 expression in TNBC and to correlate claudin 4 expression with AR status and Ki-67 expression. Paraffin blocks obtained from 56 female patients with triple-negative primary invasive ductal breast carcinomas were analyzed for claudin 4, AR, and Ki-67 immunohistochemical expression. High levels of claudin 4 expression were detected in 66.1% of TNBC cases. There was a significant positive correlation with age, tumor size, grade, nodal status, metastasis, and Ki-67 expression (all P < .05) and negative correlation with AR status (P < .001). Androgen receptor showed positivity in 29 cases (51.78%). There was a statistical negative correlation with the all the studied clinicopathologic parameters, claudin 4 and Ki-67 expression. High claudin 4 expression, negative AR expression, and high Ki-67 index would provide a strong prognostic power to differentiate the patients with worse outcome among TNBC patients. Moreover, target treatment for TNBC cells expressing claudin 4 or AR enriched would be valuable for future therapies. 10.1016/j.anndiagpath.2014.10.003
Androgen Receptor (AR), E-Cadherin, and Ki-67 as Emerging Targets and Novel Prognostic Markers in Triple-Negative Breast Cancer (TNBC) Patients. Ricciardi Giuseppina Rosaria Rita,Adamo Barbara,Ieni Antonio,Licata Luana,Cardia Roberta,Ferraro Giuseppa,Franchina Tindara,Tuccari Giovanni,Adamo Vincenzo PloS one BACKGROUND:TNBC is an aggressive subset of breast cancer (BC) without specific target therapy. METHODS:This observational, retrospective study included 45 cases of TNBC. The aim of this study was to evaluate the expression of the AR, E-cadherin and Ki-67 in relation to histological type, time to relapse and overall survival (OS). Immunohistochemistry (IHC) was carried out on formalin-fixed paraffin-embedded tumor samples obtained from patients defined TNBC. RESULTS:The AR was positive (IHC >10%) in 26.6%. E-cadherin (CDH1) expression was considered positive if the score was ≥ 2. This expression was negative in 53.3% cases. The Ki-67 index was ≥ 20% in 37.7%. Univariate analyses showed that AR, CDH1 and Ki-67 are significantly associated with OS. Multivariate analysis showed that AR and Ki-67 expression are independent variables associated with OS. The statistical analysis showed that patients with AR negative and Ki-67 positive expression have a significant correlation with poor outcome. CONCLUSIONS:Our data suggest that the combination of AR and E-cadherin expression as well as Ki-67 status might be useful prognostic markers in TNBC. Hence, these molecular determinants could play an interesting role to classify subgroups of TNBC. 10.1371/journal.pone.0128368
Clinicopathological significance of androgen receptor, HER2, Ki-67 and EGFR expressions in salivary duct carcinoma. Masubuchi Tatsuo,Tada Yuichiro,Maruya Shin-ichiro,Osamura Yoshiyuki,Kamata Shin-etsu,Miura Kouki,Fushimi Chihiro,Takahashi Hideaki,Kawakita Daisuke,Kishimoto Seiji,Nagao Toshitaka International journal of clinical oncology BACKGROUND:Salivary duct carcinoma (SDC) is a highly aggressive disease which often metastasizes to distant sites, and there is no established standard therapy for this systemic disease. Given that SDC is biologically similar to breast and prostate cancer, anti-androgenic receptor (AR) and anti-human epidermal growth factor receptor 2 (HER2) therapies have the potential to exert effects, not only on patients with breast and prostate cancer but also on those with SDC. METHODS:The expression levels of HER2, epidermal growth factor receptor (EGFR), Ki-67, and AR were assessed in 32 patients with SDC, and their correlations with overall survival (OS) and disease-free survival (DFS) were analyzed retrospectively. SDC was classified into five subtypes using a method similar to that used for breast cancer. RESULTS:Anti-AR, HER2, and EGFR were positive in 23 (71.9 %), 14 (43.8 %), and 26 (81.3 %) cases, respectively. One or more of these 3 factors were positive in 30 (93.8 %) cases. The Ki-67 labeling index was greater than 15 % in all cases. While molecular status did not correlate with OS, EGFR and AR positivity were significantly associated with DFS in univariate analysis. Multivariate analysis revealed that EGFR was the only independent predictor of DFS. CONCLUSIONS:The statuses of some molecules are useful to predict DFS in patients with SDC. Ki-67 overexpression suggests that cytotoxic agents are effective for SDC. Since the majority of SDCs express AR, HER2, and/or EGFR, assessing and targeting these molecules are promising strategies to improve the prognosis of unresectable, metastatic or recurrent SDC, and a classification system according to the molecular expression status may be useful to select appropriate therapy. 10.1007/s10147-014-0674-6
The importance of EGFR as a biomarker in molecular apocrine breast cancer. Liu Xiaozhen,Feng Changyun,Liu Junjun,Liu Jian,Li Congying,Xu Cong,Niu Yun Human pathology Molecular apocrine breast cancer (MABC) is a molecular subtype with a poor prognosis, and there is urgent need to find new therapeutic targets. Epidermal growth factor receptor (EGFR) plays an important part in regulating the biological behavior of tumor cells, and EGFR-targeted drugs have already been used in therapy for lung and colorectal cancers. The purpose of this study was to analyze the significance of EGFR expression in MABC. A total of 400 patients with invasive breast cancer were analyzed, including 200 MABC and 200 non-MABC cases. Immunohistochemistry and immunofluorescence were carried out to evaluate the expression of estrogen receptor, progesterone receptor, androgen receptor (AR), EGFR, epidermal growth factor receptor 2 (HER2), and other biomarkers. Two hundred twelve (53%) cases were positive for EGFR expression, including 173 MABC and 39 non-MABC cases. EGFR expression was positively associated with AR expression in MABC, as well as with more advanced tumor stage and high Ki67 expression. Patients with EGFR expression had worse outcomes than those without. As a prognosis biomarker, EGFR was significantly associated with poorer clinical outcomes, and the co-expression of EGFR and HER2 often predicted worse outcomes in MABC. This study suggests that the identification of new targets such as HER2 and EGFR may help with assessing the prognosis of patients with MABC. Using both AR and EGFR as therapeutic targets may be especially important in MABC and may help to guide the choice of suitable treatments for individual breast cancer patients. 10.1016/j.humpath.2018.01.016
Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERα-positive breast cancer. Ciupek Andrew,Rechoum Yassine,Gu Guowei,Gelsomino Luca,Beyer Amanda R,Brusco Lauren,Covington Kyle R,Tsimelzon Anna,Fuqua Suzanne A W Breast cancer research and treatment Tamoxifen (Tam) resistance represents a significant clinical problem in estrogen receptor (ER) α-positive breast cancer. We previously showed that decreased expression of Rho guanine nucleotide dissociation inhibitor (Rho GDI) α, a negative regulator of the Rho GTPase pathway, is associated with Tam resistance. We now discover that androgen receptor (AR) is overexpressed in cells with decreased Rho GDIα and seek to determine AR's contribution to resistance. We engineered ERα-positive cell lines with stable knockdown (KD) of Rho GDIα (KD cells). Resistance mechanisms were examined using microarray profiling, protein-interaction studies, growth and reporter gene assays, and Western blot analysis combined with a specific AR antagonist and other signaling inhibitors. Tam-resistant tumors and cell lines with low Rho GDIα levels exhibited upregulated AR expression. Microarray of Rho GDIα KD cells indicated that activation of EGFR and ERα was associated with Tam treatment. When AR levels were elevated, interaction between AR and EGFR was detected. Constitutive and Tam-induced phosphorylation of EGFR and ERK1/2 was blocked by the AR antagonist Enzalutamide, suggesting that AR-mediated EGFR activation was a mechanism of resistance in these cells. Constitutive ERα phosphorylation and transcriptional activity was inhibited by Enzalutamide and the EGFR inhibitor gefitinib, demonstrating that AR-mediated EGFR signaling activated ERα. Tam exhibited agonist activity in AR overexpressing cells, stimulating ERα transcriptional activity and proliferation, which was blocked by Enzalutamide and gefitinib. We describe a novel model of AR-mediated Tam resistance through activation of EGFR signaling leading to ER activation in ERα-positive cells with low expression of Rho GDIα. 10.1007/s10549-015-3609-7
The expression of calpain-1 and androgen receptor in breast cancer and their correlation with clinicopathological characteristics: An immunohistochemical retrospective study. Rajković-Molek Koraljka,Mustać Elvira,Avirović Manuela,Georgev Paula,Demaria Martina,Aničić Josip,Ban Josipa,Babarović Emina Pathology, research and practice Breast cancer is a heterogeneous disease with different biological outcome and ability to acquire resistance to therapy. The calpain family of proteases and androgen receptor (AR) are implicated in breast cancer pathogenesis and progression and are potential targets for novel treatment regimens. The aim of this study was to investigate the expression of calpain-1 and AR in breast cancer and to correlate their expression with clinicopathological variables and prognosis of patients. In this study we enrolled 219 breast cancer patients with long term follow-up information available. Immunohistochemical methods on a tissue microarray were used to investigate expression of calpain-1 and AR in tumor cells. The expression of calpain-1 and AR both differed significantly between the tumor subtypes of patients (p = 0.002 and p = 0.042 respectively). High calpain-1 expression was associated with patient's age over 50 years (p = 0.005) and positive ER status (p = 0.009), but not with other clinicopathological variables. Women with AR negative breast cancers were more likely to be older (p = 0.016), to have bigger tumors (p = 0.032), higher stage of the disease (p = 0.026), presence of exulceration (p = 0.017), negative ER status (p = 0.007) and higher Ki-67 proliferative index (p = 0.027). Calpain-1 expression was not associated with breast cancer specific overall survival in the total cohort of patients, however low calpain-1 expression was associated with adverse survival (p = 0.018) in triple negative subgroup of patients. Low calpain-1 expression was also associated with significantly shorter 5-year disease-free survival in total cohort of patients (p = 0.03). AR status was not associated with overall and disease-free survival of patients. This study has demonstrated that the expression of calpain-1 and androgen receptors are associated with important clinicopathological variables. The expression of calpain-1 was associated with improved disease-free survival of all analyzed patients and with improved overall survival of triple negative breast cancer patients. 10.1016/j.prp.2020.153068