Androgen receptor is frequently expressed in HER2-positive, ER/PR-negative breast cancers

Abstract

The estrogen receptor (ER)/progesterone receptor (PR)-negative breast carcinomas (BCs) encompass three molecular subtypes: one with human epidermal growth factor receptor 2 (HER) overexpression, one normal like, and the triple negative. The androgen receptor (AR) is expressed in 70-90% of invasive BCs. The aim of our study is to detect the expression of AR in a series of ER/PR-negative BCs to ascertain if there is clinical significance in relation to BC molecular subtypes. A immunohistochemical study for all receptors and cytokeratin expression was performed in 232 cases of ER/PR-negative BCs. According to cytokeratin expression, BCs were classified into two groups: luminal-type BCs (44.2%) and basal-like-type BCs (55.8%). According to the expression of HER2, 59.3% were triple-negative BCs (when ER, PR, and HER2 were negative) and 40.7% were HER2-positive BCs. AR expression was observed in 128 tumors (56.6%). One hundred and ten cases (48.8%) had >10% and 18 (7.8%) had <10% of positively stained cells. AR immunoreactivity was found in 31.2% basal-like BCs, while in the luminal group 71.1% of cases were positive, showing highly significant correlation (p < 10⁻⁸). Regarding HER2 status, 76.7% of HER2-positive BC cases were AR positive compared with only 30.4% of triple-negative BC types, showing a strong statistically significant correlation. In conclusion, we show that AR is frequently expressed in ER/PR-negative BCs and that expression of HER2 and AR is highly correlated (p < 0.005). Our results point out the role of AR and HER2 in the pathogenesis of BCs and suggest the potential role of AR in clinical management of ER/PR-negative BCs.

The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data

“…According to this theory, ER À tumors could also be stimulated via androgen activity, and depending on testosterone serum levels and AR positivity, either through EGFR or direct stimulation via androgen pathway (58). Another notable finding of our clinical meta-analysis is the worse prognostication conferred by AR positivity for women with HER2 þ ER À (Her2-enriched) disease, albeit the analysis included three studies with 358 patients (7,11,44). Similar findings have been reported, with AR positivity associated with worse clinical outcome among HER2 þ (7) as well as patients with HER2…”

“…These studies indicate that the frequency of AR positivity differs between different breast cancer subtypes; the highest positivity observed in ER-positive tumors in up to 80%-90% (6)(7)(8)(9)(10) and the lowest in triple-negative (TN) tumours, in up to 30% (6,7,11). Of note, a phase II trial assessing enzalutamide in metastatic TNBC, reported AR positivity (defined as !1%) in 79% of 404 cases analyzed (12).…”

Postmenopausal Serum Sex Steroids and Risk of Hormone Receptor–Positive and -Negative Breast Cancer: a Nested Case–Control Study

“…This local conversion of androgens into estrogens within breast tissue is likely to be a relevant physiologic mechanism especially with respect to the development of ER-responsive tumors which, as discussed above, may also include some fraction of tumors that do not express ER-alpha any longer at the time of their clinical manifestation. Almost all ER-positive tumors are also androgen receptor (AR) positive (40), however, and the same is true for a considerable proportion of ER-negative breast carcinomas (41). Furthermore, the ER-negative/PR-negative/AR-positive breast tumor Figure 2.…”

Cinical Significance of Androgen Receptor, CK-5/6, KI-67 and Molecular Subtypes in Breast Cancer

“…Loss of AR expression is usually associated with early onset, high grade tumors negative for ER, PR and HER2 (12). Although the lowest AR expression was observed in TN cancers (24), up to 30% of them were positive for AR (10,13,25). That's why it was suggested that AR could be a potential target in management of AR-positive TN breast cancers in future.…”