Androgen Receptor In Breast Cancer Research Articles

The role of androgen receptors in breast cancer

BackgroundBreast cancer is a heterogenous group of diseases with steroid hormone dependant carcinogenesis. Along with Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal growth factor Receptor 2 (HER2), androgen receptor (AR) is now emerging to play key role in disease progression of various molecular breast cancer subtypes especially triple negative breast cancers. Aim of this study was to find out prevalence of AR positivity in all breast cancers, correlation of ER, PR, HER2 and Ki67 index with AR positivity. To find out correlation of AR positivity with histological grade. MethodsThis was a descriptive cross-sectional study done on 55 primary breast carcinoma cases. Routine Hematoxylin and Eosin stain as well as immunohistochemical ER, PR, HER2/neu, Ki67 and AR stain were done. The outcome was assessed in the form of relationship between AR and ER, PR, HER2 status and Ki-67 index and histopathological grade. ResultsAR positivity was seen in 69% of all breast cancers. AR positivity was seen in 8% of triple negative breast cancers. High Ki67 index showed 55% AR positivity. Grade II breast cancers showed 42% AR positivity. ConclusionCases with triple negative breast cancers have worst prognosis. Unlike targeted novel hormone therapy (tamoxifen) in luminal cancers and monoclonal antibody (trastuzumab) in her2 enriched cancers, AR is looked upon as a target to treat triple negative breast cancer. However, the existing controversies demand more AR related studies.

Tissue Microarray Immunohistochemical Staining for Androgen Receptor in Breast Cancer in a Ghanaian Cohort.

Despite the advancement in therapy, breast cancer still remains the most common malignancy in women globally due in part to its heterogeneity. Triple-negative breast cancer (TNBC) represents up to 20% of all breast cancer variants, an aggressive disease with poorer outcomes compared to other breast cancer subtypes. No targeted therapies are currently approved for TNBC, and newer treatment approaches are seriously needed. Androgen receptor (AR), another hormonal receptor, is often expressed in breast cancer, and its role depends on the relative levels of circulating estrogens and androgens. This study aimed to assess the expression of AR in breast cancer in a tertiary hospital in Ghana. Immunohistochemical staining for AR was performed on tissue microarray (TMA) blocks, of which estrogen receptor, progesterone receptor, and Her-2/neu had already been done. 197 cases were suitable for the study. Results from the immunostaining were analyzed using the SPSS version 23 for descriptive statistics and correlations (χ2 and Pearson tests). 197 TMA cases were used. TNBCs constitute 61.9% of the cancers. The majority of these tumors were grade III, ductal carcinoma NST. The mean age was 49.86 ± 14.09, and the modal age group was 40-49 years. Our cases showed 23% AR expression in triple-negative cancers. The study also established that AR is more frequently expressed in low-grade tumors compared to high-grade ones. There is an appreciable level of AR expression in our cases; however, most are quadruple negative. However, AR is more frequently expressed in low-grade tumors than high-grade ones.

Tissue microarray immnunohistochemical staining for androgen receptor in breast cancer in a Ghanaian cohort

Abstract Introduction/Objective Despite the advancement in therapy, breast cancer still remains the commonest malignancy in women globally due in part to its heterogeneity. Triple negative breast cancer (TNBC) represents up to 20% of all breast cancer variants, an aggressive disease with poorer outcomes compared to other breast cancer subtypes. No targeted therapies are currently approved for TNBC, and newer treatment approaches are seriously needed. Androgen receptor (AR), another hormonal receptor, is often expressed in breast cancer and its role depends on the relative levels of circulating estrogens and androgens. This study aims to assess the expression of AR in breast cancer in a tertiary hospital in Ghana Methods/Case Report Immunohistochemical staining for AR was performed on tissue microarray (TMA) blocks of which ER, PR, Her-2/neu had already been done. 197 cases were suitable for the study. Results from the immunostaining were analysed using SPSS version 23 for descriptive statistics and correlations (X2 and Pearson tests) Results (if a Case Study enter NA) 197 TMA cases were used. TNBCs constitute 61.9% of the cancers. The majority of these tumours were grade III, ductal carcinoma NST. The mean age was 49.86±14.09 and the modal age group was the 40-49 years. Our cases showed 23% AR expression in triple negative cancers. The study also established that AR is more frequently expressed in low grade tumours compared to the high-grade ones. Conclusion There is appreciable level of AR expression in our cases but most are quadruple negative. However, AR is more frequently expressed in low grade tumours than high grade ones

Androgen receptor in breast cancer and its clinical implication

Androgen receptor in breast cancer and its clinical implication

Adrenal Steroids and Resistance to Hormonal Blockade of Prostate and Breast Cancer.

Prostate cancer and breast cancer are sex-steroid-dependent diseases that are driven in major part by gonadal sex steroids. Testosterone (T) is converted to 5α-dihydrotestosterone, both of which stimulate the androgen receptor (AR) and prostate cancer progression. Estradiol is the major stimulus for estrogen receptor-α (ERα) and proliferation of ERα-expressing breast cancer. However, the human adrenal provides an alternative source for sex steroids. A number of different androgens are produced by the adrenals, the most abundant of which is dehydroepiandrosterone (DHEA) and DHEA sulfate. These precursor steroids are subject to metabolism by peripherally expressed enzymes that are responsible for the synthesis of potent androgens and estrogens. In the case of prostate cancer, the regulation of one of these enzymatic steps occurs at least in part by way of a germline-encoded missense in 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which regulates potent androgen biosynthesis and clinical outcomes in men with advanced prostate cancer treated with gonadal T deprivation. The sex steroids that drive prostate cancer and breast cancer require a common set of enzymes for their generation. However, the pathways diverge once 3-keto, Δ4-androgens are generated and these steroids are either turned into potent androgens by steroid-5α-reductase, or into estrogens by aromatase. Alternative steroid receptors have also emerged as disease- and treatment-resistance modifiers, including a role for AR in breast cancer and glucocorticoid receptor both in breast and prostate cancer. In this review, we integrate the commonalities of adrenal steroid physiology that regulate both prostate and breast cancer while recognizing the clear distinctions between these diseases.

Androgen receptor in breast cancer: The "5W" questions.

Androgen receptor (AR) is expressed in 60-70% of breast cancers (BCs) and the availability of anti-AR compounds, currently used for treating prostate cancer, paves the way to tackle specifically AR-positive BC patients. The prognostic and predictive role of AR in BC is a matter of debate, since the results from clinical trials are not striking, probably due to both technical and biological reasons. In this review, we aimed to highlight WHAT is AR, describing its structure and functions, WHAT to test and HOW to detect AR, WHERE AR should be tested (on primary tumor or metastasis) and WHY studying this fascinating hormone receptor, exploring and debating on its prognostic and predictive role. We considered AR and its ratio with other hormone receptors, analyzing also studies including patients with ductal carcinoma in situ and with early and advanced BC, as well. We also emphasized the effects that both other hormone receptors and the newly emerging androgen-inducible non coding RNAs may have on AR function in BC pathology and the putative implementation in the clinical setting. Moreover, we pointed out the latest results by clinical trials and we speculated about the use of anti-AR therapies in BC clinical practice.

Phase 3 ENABLAR-2 study to evaluate enobosarm and abemaciclib combination compared to estrogen-blocking agent for the second-line treatment of AR+, ER+, HER2- metastatic breast cancer in patients who previously received palbociclib and estrogen-blocking agent combination therapy.

TPS1121 Background: Targeting the androgen receptor (AR) may be the next important endocrine therapy for advanced breast cancer. The AR has been demonstrated to be a tumor suppressor when activated. Enobosarm is an oral selective AR targeting agonist that activates the AR in breast cancer. Preclinical studies in CDK4/6 inhibitor resistant PDX models demonstrated combinatorial synergistic activity of enobosarm plus CDK 4/6 inhibitors. An open-label, Phase 2 study, was conducted in 136 women with heavily pretreated ER+ HER2- metastatic breast cancer that were randomized to oral daily enobosarm at a dose of 9 or 18 mg. The efficacy evaluable (EE) group were patients that were AR positive (> 10% AR nuclear staining). In the EE population with measurable disease at baseline, 10 patients had received prior endocrine therapy + a CDK 4/6 inhibitor. Subsequent treatment with enobosarm resulted in a clinical benefit rate of 50% and the best overall response rate (ORR) was 30% (2CRs and 1 PR). Of the 10 patients, 7 had AR nuclear staining ≥40%. None of the patients with AR nuclear staining < 40% responded to enobosarm. Although a small subset of the study, it appears that enobosarm has activity in patients who had ≥40% AR staining and who had progressed on standard endocrine therapy with a CDK 4/6 inhibitor. Overall, treatment with enobosarm was well tolerated with significant positive effects on quality-of-life measurements. Methods: The ENABLAR-2 trial is an ongoing Phase 3, randomized, open-label, efficacy and safety study in patients with AR+ ER+ HER2- MBC with AR nuclear staining of ≥40%, who have progressed after one line of systemic therapy comprising estrogen blocking agent and palbociclib. The planned sample size is 186 patients randomized 1:1 to enobosarm + abemaciclib OR fulvestrant if the first line of therapy for MBC was a non-steroidal AI plus palbociclib, until disease progression, toxicity, or loss of clinical benefit. If first line therapy for metastatic breast cancer was fulvestrant plus palbociclib, then the patient will be randomized 1:1 to either enobosarm + abemaciclib OR an AI. Randomization will be stratified by AR% nuclear staining, ≥60% versus < 60%, as well as by estrogen blocking agent such that each cohort will have the same number of subjects previously receiving fulvestrant + palbociclib in first line therapy. The key objectives are to determine the safety and efficacy of enobosarm and abemaciclib combination versus an alternative estrogen blocking agent with the primary endpoint of PFS. Secondary endpoints include ORR, duration of response, overall survival, change from baseline in Short Physical Performance Battery (SPPB), change in EORTC Quality of Life Questionnaire (EORTC-QLQ) and change in body composition as measured by DEXA. Clinical trial information: NCT05065411.

206TiP Randomized, multicenter, international phase III ARTEST study to evaluate enobosarm versus active control for the treatment of AR+ ER+ HER2- metastatic breast cancer in patients who previously received an estrogen-blocking agent and a CDK 4/6 inhibitor

Targeting the androgen receptor (AR) may be the next important endocrine therapy for advanced breast cancer. Enobosarm is an oral selective AR targeting agonist that activates the AR in breast cancer. Enobosarm has an extensive clinical experience in 25 clinical trials including in 2 phase 2 studies conducted in patients (pts) with AR+ ER+ HER2- metastatic breast cancer (MBC). An open-label, parallel design phase 2 study, was conducted in 136 women with heavily pretreated ER+ HER2- MBC that were randomized to oral daily enobosarm at a dose of 9 or 18 mg.

Immunohistochemical study of GATA3 and Androgen receptors in breast cancer

Immunohistochemical study of GATA3 and Androgen receptors in breast cancer

Abstract OT2-17-01: Randomized, multicenter, international phase 3 ARTEST study to evaluate the efficacy and safety of enobosarm versus active control for the treatment of AR+ ER+ HER2- metastatic breast cancer in patients who progressed on a nonsteroidal aromatase inhibitor, fulvestrant and CDK 4/6 inhibitor

Abstract Targeting the androgen receptor (AR) may be the next important endocrine therapy for women with advanced breast cancer. AR is the most abundantly expressed steroid receptor in breast cancer and has been demonstrated to be a tumor suppressor when activated. Enobosarm is an oral selective nonsteroidal agonist that activates the AR in breast cancer. Enobosarm has an extensive clinical experience in 25 clinical trials and 1,450 dosed subjects including in breast cancer where three Phase 2 studies have been conducted two of which were in women (158 subjects) who had AR+/ER+/HER2- metastatic breast cancer (MBC).The larger Phase 2 clinical trial (G200802) evaluated 9mg and 18mg enobosarm daily oral dosing in 136 women with ER+/HER2- MBC who previously responded to endocrine treatment. Patients were heavily pretreated having progressed on an average of 3 endocrine treatments and 90% had prior chemotherapy. Enobosarm showed efficacy activity in the overall study with a clinical benefit rate at 6 months of 32% (95% CI: 19.5%,46.7%) for the 9 mg and 29% (95% CI: 17.1%,43.1%) for the 18 mg evaluable cohorts. Quality of life assessments showed significant improvement from baseline for both enobosarm cohorts (p=0.002). Enobosarm was well tolerated at both doses. In a post-hoc analysis in all patients (9mg and 18mg) with known AR status and measurable disease (n=84), AR expression in breast. cancer tissue (%AR nuclei staining) correlated with efficacy outcomes. When comparing AR nuclei staining ≥40% (n=47) compared to patients with an AR nuclei staining <40% (n=37): 1) Clinical benefit rate at 6 months was 52% for AR ≥40% and 14% for AR <40% (p<0.0004); 2) Overall response rate (ORR) was 34% for AR ≥40% and 2.7% for AR <40% (p<0.0003; 3) Radiographic was 5.47 months for AR ≥40% and 2.72 months for AR <40% (p<0.001). The ARTEST trial is a Phase 3 multicenter, international randomized, open-label, two treatment arm, efficacy and safety study. Approximately, 210 subjects with AR+ ER+ HER2- MBC and with AR nuclei staining ≥40% will be randomized 1:1 to either enobosarm 9mg oral daily dose or an active comparator (either exemestane ± everolimus or selective estrogen receptor modulator; physician’s choice). Subjects will be treated until disease progression is observed or an unacceptable adverse event is observed. The primary endpoint of the study is imaging based progression free survival as measured by RECIST 1.1. The secondary objectives/endpoints on this study include the ORR, duration of response, overall survival, and change from baseline in Short Physical Performance Battery (SPPB). The study is planned to begin enrollment in Q3 2021. Citation Format: Adam Brufsky, Hannah Linden, Hope Rugo, Charles Vogel, Joyce A O'Shaughnessy, Robert H Getzenberg, K. Gary Barnette, Domingo Rodriguez, Mitchell S Steiner, Erica Mayer. Randomized, multicenter, international phase 3 ARTEST study to evaluate the efficacy and safety of enobosarm versus active control for the treatment of AR+ ER+ HER2- metastatic breast cancer in patients who progressed on a nonsteroidal aromatase inhibitor, fulvestrant and CDK 4/6 inhibitor [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-17-01.

The Association of RGS2 and Slug in the Androgen-induced Acquisition of Mesenchymal Features of Breast MDA-MB-453 Cancer Cells

ABSTRACT Background Epithelial-mesenchymal transition (EMT) of tumor cells is a prerequisite to cancer cell invasion and metastasis. This process involves a network of molecular alterations. Androgen receptor (AR) plays an important role in the biology of breast cancers, particularly those dependent on AR expression like luminal AR (LAR) breast cancer subtype. We have recently reported that the AR agonist, dihydrotestosterone (DHT), induces a mesenchymal transition of MDA-MB-453 cells, concomitant with transcriptional up-regulation of Slug and regulator of G protein signaling 2 (RGS2). Objective The role of Slug and RGS2 in mediating the DHT-induced effects in these cells was investigated. Methods MDA-MB-453 cells were used as a model system of LAR breast cancer. Immunofluorescence was used to examine cell morphology and protein localization. Protein expression was analyzed by immunoblotting. Protein localization was confirmed by cell fractionation followed by immunoblotting. Protein-protein interaction was confirmed by co-immunoprecipitation followed by immunoblotting. Transwell membranes were used to assess cell migration. Transfection of cells with siRNA molecules that target Slug and RGS2 mRNA was utilized to delineate the modes of action of these two molecules. Results Treatment of MDA-MB-453 cells with DHT induced the expression of both proteins. In addition, AR-Slug, AR-RGS2, and Slug-RGS2 interactions were observed shortly after AR activation. Knocking down Slug abrogated the basal, but not the DHT-induced, cell migration and blocked DHT-induced mesenchymal transition. On the other hand, RGS2 knocked-down cells had an increased level of Slug protein and assumed mesenchymal cell morphology with induced migration, and the addition of DHT further elongated cell morphology and stimulated their migration. Inhibition of AR or β-catenin reverted the RGS2 knocked-down cells to the epithelial phenotype, but only inhibition of AR blocked their DHT-induced migration. Conclusions These results suggest the involvement of RGS2 and Slug in a complex molecular network regulating the DHT-induced mesenchymal features in MDA-MB-453 cells. The study may offer a better understanding of the biological role of AR in breast cancer toward devising AR-based therapeutic strategies.

Androgen Receptor Expression in Triple-negative Breast Cancer and its Relation with Epidermal Growth Factor Receptor, CD 105, and Clinicopathological Parameters

Background: Triple-negative breast cancers (TNBC) are the tumors lacking expression of estrogen receptors, progesterone receptors, and human epidermal growth factor 2. The highest level of androgen receptors (AR) expression belongs to the Luminal androgen receptor subtype. AR is expressed in 70 to 90% of primary breast cancers. The biological role of AR in breast cancer continues to emerge. The overexpression of epidermal growth factor receptor (EGFR) has been previously studied in TNBC, where it was found to be associated with poor prognosis. In the evaluation of neovascularization, CD105 (endoglin) was found to be superior to CD34 and CD31 owing to its greater affinity for endothelial cells in tumor-related angiogenic tissue. We conducted the present work to assess the expression profile of androgen receptor in TNBC cases and its correlation with other clinicopathological parameters, EGFR and CD 105, in order to evaluate its clinical significance. Method: This retrospective study included 50 histologically confirmed breast cancer patients who were proven to be triple-negative based on immunohistochemical study. Formalin-fixed tissue blocks with tumor were chosen for immunohistochemical staining for AR, EGFR, CD105, and Ki 67. Results: Positive AR expression was associated with older age, postmenopausal status, negative nodes, and grade II tumors. AR was inversely correlated with EGFR, while there was no correlation between AR and both Endoglin and Ki 67. Conclusion: AR-positive TNBC may be a subtype of breast cancer with unique characteristics that could make it ideal for antiandrogen endocrine therapy. EGFR and Endoglin's distinct expression indicated that they might be unique biomarkers for targeted therapy and prognosis.

The importance of androgen receptors in breast cancer.

Breast cancer (BC) is the most common malignancy among women worldwide, and one of the leading causes of cancer-related deaths in females. For the breast malignant tumors there are numerous targeted therapies, depending on the receptors expressed. Regulating the process of epithelial-mesenchyme transcription, the steroid nuclear receptors are important in invasion and progression of BC cells. Till now, it is known that androgen receptor (AR) is present in about 60-80% of BC cells but, unfortunately, there is no targeted therapy available yet. We revised the recent literature that included the AR mechanism of action in patients diagnosed with breast cancer, the preclinical, retrospective and clinical studies and the aspects related to the prognosis of these patients, depending on the molecular subtype. A total of 12 articles were eligible for this review. AR positivity was assessed using immunohistochemistry. Herein, neither 1 nor 10% cut-points were robustly prognostic. AR was an independent prognostic marker of BC outcome, especially in triple negative BC group. AR is a potential targeted pathway which can improve the prognostic of AR positive patients with BC. Further preclinical and clinical studies are necessary to clarify the mechanism of action and to establish the drugs which can be used, either alone or in combination.

Abstract OT-09-08: Solti-1502 aRIANNA: Targeting PAM50 HER2-enriched intrinsic subtype with enzalutamide in hormone receptor-positive/HER2-negative metastatic breast cancer

Abstract Background Pre-clinical evidence and retrospective studies suggest that PAM50 HER2-Enriched (HER2-E), hormone receptor-positive (HR+)/HER2-negative tumors have estrogen receptor (ER)-independency and poor prognosis, but seem to have androgen receptor (AR)-addiction (1). Enzalutamide (EZM) is a potent inhibitor of androgen receptor signaling (3). AR expression has been shown to induce resistance to both tamoxifen and aromatase inhibitors in estrogen receptor HR-expressing cell lines (4,5) The hypothesis of the ARIANNA trial is that EZM induces a significant proliferative arrest in PAM50 HER2-E, HR+/HER2-negative advanced breast cancer (BC), leading to clinical benefit in this poor prognosis population. Methods ARIANNA is an exploratory, phase II clinical trial in two independent cohorts evaluating the effect of EZM on proliferation after 2 weeks (+7 days window) on treatment in pre- or post-menopausal female or male patients with endocrine-resistant, locally advanced or metastatic HR+/HER2-negative BC. Cohort A will include 22 patients with PAM50 HER2-E HR+/HER-negative tumors and Cohort B (control group) will include 22 patients with PAM50 Luminal A/B HR+/HER2-negative tumors. Fresh tumor biopsy will be obtained at screening and sent to central laboratory for PAM50 subtyping determination to confirm the molecular subtype status prior to study treatment initiation, and to determine PAM50 11-gene proliferation-related signature. Patients with PAM50 Basal-like or Normal-like tumors will be excluded. Patients will receive EZM 160 mg once a day (QD). After 2 weeks on treatment, a tumor biopsy from the same baseline lesion (or, if not feasible, a lesion in the same organ) will be obtained for the purpose of the primary endpoint analysis. After this on-treatment biopsy, exemestane 50mg QD can be added to EZM at physician’s discretion. Tumor assessment will be performed at screening and every 8 weeks thereafter. Treatment will be continued until disease progression, unacceptable toxicity, investigator’s decision or withdrawal of consent. An optional tumor biopsy will be collected at the end of treatment. The primary objective is to evaluate the anti-proliferative effect of EZM after 2 weeks of treatment in patients with HER2-E HR+/HER2-negative tumors, measured as relative changes in the PAM50 11-gene proliferation-related signature by the PAM50 nCounter-based assay between baseline and on-treatment tumor biopsies. Secondary objectives include: anti-proliferative effect of EZM after 2 weeks of treatment in patients included in Cohort B (control group), safety, overall response rate, progression-free survival, and further correlative molecular analyses both at the tumor tissue (IHC, RNA and DNA) and ctDNA level for both cohorts. The trial will enroll patients in 8 Spanish sites and recruitment period will be 18 months. Funding was granted by Breast Cancer Research Foundation and drug was supplied by Astellas Pharma Global Development, Inc./Pfizer, Inc. Trial identification: NCT04142060 1. Cochrane DR, Bernales S, Jacobsen BM, Cittelly DM, Howe EN, D’Amato NC, et al. Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res. 2014;16:R7. 3. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer. Science. 2009;324:787-90. 4. Rechoum Y, Rovito D, Iacopetta D, Barone I, Andò S, Weigel NL, et al. AR collaborates with ERα in aromatase inhibitor-resistant breast cancer. Breast Cancer Res Treat. 2014;147:473-85. 5. De Amicis F, Thirugnansampanthan J, Cui Y, Selever J, Beyer A, Parra I, et al. Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat. 2010;121:1-11 Citation Format: Mafalda Oliveira, Sonia Pernas, Mireia Margelí, Salvador Blanch, Barbara Adamo, Javier Salvador Bofill, Diana Moreno, Xavier Gonzalez-Farré, José Rios, Charles M Perou, Aleix Prat, Tomás Pascual, Juan M Ferrero-Cafiero, Patricia Villagrasa, Luis Manso. Solti-1502 aRIANNA: Targeting PAM50 HER2-enriched intrinsic subtype with enzalutamide in hormone receptor-positive/HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-08.

Abstract PS5-36: Computational modeling of androgen receptor (AR) and estrogen receptor as predictive biomarkers of response to AR agonists and antagonists

Abstract Background: Androgen receptor (AR) is expressed in 60%-90% of breast cancers. The role of AR in breast cancer largely depends on estrogen receptor (ER) status and remains controversial. In ER+ cancers, AR expression is associated with improved prognosis. Enzalutamide (ENZ), an AR antagonist, impairs AR signaling, inhibits ER+/AR+ breast cancer cell proliferation and has been shown to mitigate resistance to anti-estrogen therapies. A recent study identified that RAD140, an AR agonist, suppressed the growth of ER+/AR+ breast cancer via stimulating AR signaling, resulting in down regulation of ERα. Both AR agonists and antagonists are effective in treating ER+ breast cancers. Identifying the subgroup of patients who most likely will benefit from an individual drug is important in clinical practice. Here, we sought to characterize the relative AR to ER levels and their relationships to drug response in ER+ breast cancers.Methods: We evaluated AR and ER expression levels among 68 samples with ER+ breast cancers. On each tumor, IHC staining for AR and ER were performed and results were scored by multiplying the percentage of positive cells by the intensity. TCGA-RPPA (reverse phase protein array) dataset was used to verify AR protein distribution in ER+ cancers. We created MCF7 and T47D cells with doxycycline-inducible AR and ER expression system to manipulate the relative AR to ER ratios and determined the antitumor activity of ENZ and RAD140 by cell proliferation assays. The levels of AR and ER in cells were measured by western blot. Linear regression was used to test the association between dose-response area under curve (AUC) and AR, ER levels. Drug preference was modeled against AR/ER expression levels (AR/ER ratios) using logistic regression.Results: Among 68 ER+ breast cancers, 69.12% were AR-positive. More than 2/3 cases (48 of 68) had more ER than AR expressed. The AR to ER ratios varied from 0 to 6. In the TCGA cohort, 84.15% of 347 ER+ patients had AR/ER ratios less than 1.The range of AR to ER ratios in TCGA dataset were comparable with our data (0.004 to 4.210). In our cell line models, the AR/ER ratios were controlled between 0.19 to 4.05. We found that the AUC of RAD140 was negatively associated with AR protein levels (P=0.008) and AR/ER ratios (P=0.013), and not significantly associated with ER expression levels. On the other hand, the AUC of ENZ was significantly negatively associated with ER protein (P=0.0016) but postiviely associated with AR/ER ratio (p=0.037). Preferred treatment comparing efficacy of the two drug can be best determined at extremes of AR/ER ratios. Using clinically relevant dosages, our model predicted that ENZ (10µM) would be a preferred treatment choice and have a better treatment efficacy compared with RAD140 when the AR/ER ratio was ≤ 0.42, whereas RAD140 (1µM) would be the preferred choice with a better treatment efficacy compared with ENZ when AR/ER ratios were ≥ 3.1 The efficacy preference of the two drugs are equivocal for AR/ER ratios between 0.42 and 3.10. Conclusion: We developed preclinical models using AR and ER expression levels to predict AR-targeting drug response. The results support the use of RAD140 in AR high patients and those with an AR/ER ratio >3.10, and enzalutamide in AR low patients and those with an AR/ER ratio <0.42. Equipoise on choice of drug was found for AR/ER ratios of 0.42-3.10. RAD140 and enzalutamide are compelling candidates for monotherapy or combination with anti-estrogen therapies in ER+/AR+ breast cancer. Future clinical validation of the models and therapeutic effect is warranted. Citation Format: Lixuan Wei, Huanyao Gao, Jia Yu, Duan Liu, Huan Zhang, Thanh Nguyen, Marie R Passow, Jodi M Carter, Richard M Weinshilboum, James N Ingle, Liewei Wang. Computational modeling of androgen receptor (AR) and estrogen receptor as predictive biomarkers of response to AR agonists and antagonists [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-36.

Androgen receptor in breast cancer: A tissue microarray-based study

Background and Aim: Breast carcinoma is the most common malignant tumor and the leading cause of cancer deaths in women. The incidence of breast cancer in India has been gradually raising accounting for 25%–33% of all cancers in women. Breast carcinomas are a heterogeneous group of tumors which show varied behavior and response to therapeutic agents. Androgen receptors (ARs) have been studied in great detail in prostate cancers, now being studied in breast cancers, but its role in breast cancer has not been elucidated completely. The aim of our study was to evaluate the expression of AR in invasive carcinoma of the breast and to evaluate its relation to estrogen receptor (ER), progesterone receptor (PR), and Human Epidermal growth factor Receptor2 (HER2) expression on tissue microarray (TMA) sections. Materials and Methods: This was a descriptive study which included 53 cases of breast carcinoma. The specimens were fixed in 10% formalin, routinely processed. A master block for TMA was made by taking 2 mm cores from paraffin blocks containing tumor. Sections were taken and stained for ER, PR, AR, and HER2. Results: A total of 53 cases were studied. Around 63% of breast carcinomas were positive for AR. Conclusion: AR expression can be used as an additional biomarker in breast carcinomas, and a large number of cases can be studied by TMA sections.

Androgen Receptor in Breast Cancer: From Bench to Bedside.

Breast cancer (BC) is one of the most common malignancies and the leading cause of cancer-related mortality in women. Androgen receptor (AR) is frequently expressed in diverse BC subtypes. Accumulating evidence has revealed that AR might be a predictive or prognostic factor and a drug target in BC. AR expression and AR pathways differ in various BC subtypes, thereby resulting in controversial inferences on the predictive and prognostic value of AR. Herein, we summarized the roles of AR in different BC subtypes and AR-targeting therapies based on preclinical and clinical studies. Moreover, we highlighted the possible efficacy of a combination therapy via exploiting the AR-related mechanisms and the research on therapeutic resistance.

The expression of calpain-1 and androgen receptor in breast cancer and their correlation with clinicopathological characteristics: An immunohistochemical retrospective study

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.

Distribution and characteristics of androgen receptor (AR) in breast cancer among women in Addis Ababa, Ethiopia: A cross sectional study.

Evaluation of the role of androgen receptor (AR) in the biology of breast cancer is an emerging area of research. There are compelling evidences that AR expression may be used to further refine breast cancer molecular subtyping with prognostic and therapeutic implications. Many studies indicated co-expression of AR with the hormonal receptors in breast cancer has a favorable prognosis. AR is also investigated by many researchers as a potential therapeutic target in treatment of breast cancer. Studies on the frequency and distribution of AR in breast cancer among Africans is barely available. Given the heightened interest to understand its role in breast cancer, we determined AR expression and assessed its association with clinicopathological parameters among Ethiopian women. In this study, 112 newly diagnosed patient with invasive breast cancer at Tikur Anbessa Specialized Hospital were enrolled. Immunohistochemical assessment of AR, ER, PR, Ki67 and HER2 were performed using tissue microarrays (TMA) constructed from their primary tumor block. Out of the 112 participants, 91 (81%) were positive for AR expression and the remaining 21 participants (19%) were negative for AR expression. Expression of AR in ER+, HER2+ and TNBC cases were 93%, 83% and 48% respectively. Our study reveals AR is expressed in a significant number of breast cancers patients and this may indicate that breast cancers cases in Ethiopia have favorable prognosis and could benefit from progresses in AR targeted treatments. Since AR expression has important consequences on the prognosis and treatment of breast cancer, further studies with an increased number of participants is necessary to confirm our reports.

The Expression and Prognostic Significance of Claudin-8 and Androgen Receptor in Breast Cancer.

PurposeClaudin-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 MethodsTwenty-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).ResultsCLDN8 was downregulated in breast cancer tissues and positively correlated with none lymph node metastasis (P=0.016), low histological grade (P=0.006), positive ER (P=0.014), positive PR (P=0.003), low Ki-67 index (P=0.017) and molecular subtypes (P=0.012). CLDN8 level was significantly associated with AR level (r=0.348; P<0.001). CLDN8 and AR co-expression was positively correlated with none lymph node metastasis (P=0.007), low histological grade (P=0.017), positive ER (P=0.019), positive PR (P=0.015) and low Ki-67 index group (P=0.038). CLDN8 and AR co-expression had a better clinical prognosis.ConclusionThe 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.