Lack of Androgen Receptor Expression Selects for Basal-Like Phenotype and Is a Predictor of Poor Clinical Outcome in Non-Metastatic Triple Negative Breast Cancer

Abstract

Background: Androgen receptor (AR) has emerged as a significant favorable prognostic indicator in estrogen receptor expressing (ER +) breast cancer (BCa); however, its clinical and biological relevance in triple negative breast cancer (TNBC) and association with cancer stem cell (CSC) markers remain ambiguous. Methods: We examined the immunohistochemical expression of AR in a cohort of stage I-III TNBC cases (n = 197) with a long-term clinical follow-up data (mean follow-up = 53.6 months). Significance of AR expression was correlated with prognostic biomarkers including cancer stem cell markers (CD44, CD24, and ALDH1), basal markers (CK5, CK14, and nestin), proliferation marker (ki-67), apoptotic marker (Bcl-2), and COX-2. Expression of CK5 and nestin was used for the categorization of TNBC into basal (TN, CK5 + , and/or nestin +) and non-basal (TN, CK5 − , and/or nestin −) phenotypes, and Kaplan-Meier curves were used for estimation of overall survival and breast cancer-specific survival (BCSS). Results: AR expression was observed in 18.8% of non-metastatic TNBC tumors. Expression of AR correlated with lower grade (P < 0.001) and conferred a favorable prognostic significance in patients with axillary lymph node metastasis (P = 0.005). Lack of AR expression correlated with expression of CSC phenotype (CD44 + /CD24 −) (P < 0.001), COX-2 (P = 0.02), basal markers (CK5: P = 0.03), and nestin (P = 0.01). Basal-like phenotype (TN, CK5 + , and/or nestin +) correlated with quadruple-negative breast cancer (QNBC) and showed a significant association with adverse prognostic markers including high proliferation index (P < 0.001), expression of COX-2 (P = 0.009), and CSC phenotype (CD44 + /CD24 − : P = 0.01). Expression of AR remained an independent prognostic indicator for improved overall survival (P = 0.003), whereas basal-like phenotype was associated with an adverse BCSS (P = 0.013). Conclusions: Assessment of AR and basal markers identified biologically and clinically distinct subgroups of TNBC. Expression of AR defined a low-risk TNBC subgroup associated with improved overall survival, whereas expression of basal markers Riaz et al. Androgen Receptor Expression in TNBC (CK5 and nestin) identified a high-risk subgroup associated with adverse BCSS. Integration of immunohistochemical analysis of AR and basal biomarkers to the assessment of TNBC tumors is expected to improve the prognostication of an otherwise heterogeneous disease.

A Systematic Review to Clarify the Prognostic Values of CD44 and CD44+CD24- Phenotype in Triple-Negative Breast Cancer Patients: Lessons Learned and The Road Ahead

“…The CD44 + CD24 -/low phenotype expression has been frequent in basal-like neoplasms than in non-basal-like neoplasms (33). Consistent with this, Riaz et al have shed light on a correlation between CD44 + CD24 -/low phenotype and basal-like TNBC in chemotherapy and radiotherapy-experienced basal-like TNBC patients (35). Among the CD44/CD24 phenotypes, CD44 + CD24 -/low has been associated with more aggressive TNBC regarding the tumor size, TMN stage, and lymph node metastasis (29).…”

“…However, in treated TNBC patients with standard chemotherapy and radiotherapy, the CD44 + CD24 -/low phenotype is inversely correlated with AR expression ( 35 ). Indeed, AR expression has been associated with improved OS and breast cancer-specific survival in treated TNBC patients ( 35 ). Consistent with this, the CD44 + CD24 -/low TNBC cells have exhibited a more aggressive histological pattern, high Ki67 score, increased vimentin, and upregulated EGFR, decreased E-cadherin, and downregulated claudin-3/4/7 compared to AR + TNBC cells ( 27 ).…”

“…The CD44 + CD24 -/Low Phenotype in Treatment-Naïve and Treated Patients and Its Cross-Talk With Chemoresistance and Metastasis Among the different CD44/CD24 phenotypes, CD44 + CD24 -/low cells have expressed a substantial AR in TNBC patients without previous chemotherapy and radiotherapy (28). However, in treated TNBC patients with standard chemotherapy and radiotherapy, the CD44 + CD24 -/low phenotype is inversely correlated with AR expression (35). Indeed, AR expression has been associated with improved OS and breast cancer-specific survival in treated TNBC patients (35).…”

Gender Differences in Urothelial Bladder Cancer. Effects of Natural Killer Lymphocyte Immunity

“…Interestingly, triple-negative breast cancers of women often express AR and might respond to ADT or AR blockade [30]. Yet, triple-negative breast cancers that lose AR expression often have characteristics of primitive basal-like cancers with poor clinical course [31]. This suggests that AR signaling may help induce new breast cancers, but "dedifferentiated" primitive cancers may downregulate AR expression because they are driven by hormoneindependent mechanisms.…”

Gender Differences in Urothelial Bladder Cancer. Effects of Natural Killer Lymphocyte Immunity

“…Interestingly, triple-negative breast cancers of women often express AR and might respond to ADT or AR blockade [36]. Yet, triple-negative breast cancers that lose AR expression often have characteristics of primitive basal-like cancers with poor clinical course [37]. This suggests that AR sig-naling may help induce new breast cancers, but "dedifferentiated" primitive cancers may downregulate AR expression because they are driven by hormone-independent mechanisms.…”