Androgen Receptor Status Is a Prognostic Marker in Non-Basal Triple Negative Breast Cancers and Determines Novel Therapeutic Options

Abstract

Triple negative breast cancers are a heterogeneous group of tumors characterized by poor patient survival and lack of targeted therapeutics. Androgen receptor has been associated with triple negative breast cancer pathogenesis, but its role in the different subtypes has not been clearly defined. We examined androgen receptor protein expression by immunohistochemical analysis in 678 breast cancers, including 396 triple negative cancers. Fifty matched lymph node metastases were also examined. Association of expression status with clinical (race, survival) and pathological (basal, non-basal subtype, stage, grade) features was also evaluated. In 160 triple negative breast cancers, mRNA microarray expression profiling was performed, and differences according to androgen receptor status were analyzed. In triple negative cancers the percentage of androgen receptor positive cases was lower (24.8% vs 81.6% of non-triple negative cases), especially in African American women (16.7% vs 25.5% of cancers of white women). No significant difference in androgen receptor expression was observed in primary tumors vs matched metastatic lesions. Positive androgen receptor immunoreactivity was inversely correlated with tumor grade (p<0.01) and associated with better overall patient survival (p = 0.032) in the non-basal triple negative cancer group. In the microarray study, expression of three genes (HER4, TNFSF10, CDK6) showed significant deregulation in association with androgen receptor status; eg CDK6, a novel therapeutic target in triple negative cancers, showed significantly higher expression level in androgen receptor negative cases (p<0.01). These findings confirm the prognostic impact of androgen receptor expression in non-basal triple negative breast cancers, and suggest targeting of new androgen receptor-related molecular pathways in patients with these cancers.

Coexpression of androgen receptor and FOXA1 in nonmetastatic triple-negative breast cancer: ancillary study from PACS08 trial

“…AR+ tumors had significantly lower nuclear grades than AR-tumors. These results are concordant with other studies, both in ER- [24,[27][28][29] and TNBC [23,25,[30][31][32][33]. These studies found an inverse correlation between AR positivity Table 2 and different proliferation markers: grade [24][25][28][29][30][31][32], mitotic score [23,25,32] or Ki67 expression [24,27,32].…”

“…However, the prognostic value of AR expression in TNBC is still a matter of debate. In some studies, better DFS and/or overall survival (OS) was observed when tumors expressed AR [25,[30][31]39,[44][45], and in one study only in the subgroup of nonbasal TNBC [33]. This was possibly due to their more favorable characteristics resulting in a more indolent subgroup of tumors.…”

HITS-CLIP reveals key regulators of nuclear receptor signaling in breast cancer

“…Expression of steroid receptors such as ER, PR and AR have been shown to define a more differentiated breast cancer phenotype, which correlates with lower tumor grade and better patient outcomes [42–45]. We speculated that if miR-9-5p was a global regulator of steroid receptors (ER and AR) and its co-factors (NCOA2-4), we could verify such an association in an independent data set.…”

Bringing androgens up a NOTCH in breast cancer

“…However, it is currently unclear how to stratify individual breast cancers based on whether they will respond favourably to androgen treatment or not. In different breast cancer cell lines, modulation of androgen signalling can have growth-inhibitory or growth-promoting effects (Birrell et al 1995, Ortmann et al 2002, Greeve et al 2004, Lyu et al 2014, reviewed in Fioretti et al (2014), and this extends to the applicability of AR expression as a prognostic marker in specific subtypes of breast cancer (Kuenen-Boumeester et al 1996, Agoff et al 2003, Peters et al 2009, Kraus et al 2010, Gasparini et al 2014. Such conflicting reports/data raise concerns for the clinical efficacy of androgen modulation in breast cancer.…”