Abstract
Estrogen receptor (ER) positive breast cancer (BC), the most abundant BC subtype, is notorious for poor response to neoadjuvant chemotherapy (NAC). The androgen receptor (AR) was reported to support estradiol-mediated ER activity in an in vitro system. Recently, ER-positive BC with fewer tumor infiltrating lymphocytes (TILs) was shown to have a better prognosis, opposite to the trend seen with ER-negative BC. We hypothesized that ER-positive BC with high expression of AR will have fewer TILs and an inferior response to NAC, but with a better prognosis. In both TCGA and METABRIC cohorts, AR expression was significantly higher in ER-positive BCs compared to ER-negatives (p < 0.001, p < 0.001, respectively) and it correlated with ER expression (R = 0.630, R = 0.509, respectively). In ER-positive tumors, AR high tumors enriched UV response down (NES = 2.01, p < 0.001), and AR low tumors enriched DNA repair (NES = −2.02, p < 0.001). AR high tumors were significantly associated with procancer regulatory T-cells, and AR low tumors were associated with anticancer immune cells, such as CD4, CD8, and Gamma-Delta T-cells and memory B-cells in ER-positive BC (p < 0.01). Further, cytolytic activity was significantly lower in AR high BC in both cohorts. Finally, AR high tumors had a significantly lower rate of attaining pathological complete response to NAC (GSE22358), but better survival. In conclusion, our results demonstrated that high AR has fewer tumor infiltrating lymphocytes as well as cytolytic activity and an inferior response to NAC, but better survival in ER-positive BC.
Highlights
Breast cancer (BC) is the most common cancer among women in the United States excluding skin cancers
Estrogen receptor (ER)-positive tumors classified by IHC in The Cancer Genome Atlas (TCGA), expressed significantly higher levels of androgen receptor (AR) mRNA expression when compared to ER-negative patients (Figure 1B)
ER-positive BC is known to have less tumor infiltrating lymphocytes (TILs) when compared to triple negative BC, it was of interest to investigate whether this mechanistic model applies in AR high tumors where we found lower infiltration of TILs among ER-positive BC
Summary
Breast cancer (BC) is the most common cancer among women in the United States excluding skin cancers. About one in eight U.S women (about 12%) will develop invasive BC in their lifetime [1]. ER-positive BC has a relatively better prognosis compared with the other subtypes [3,4], it is well known to have less tumor infiltrating lymphocytes (TIL) [5,6], and less responsiveness to neoadjuvant chemotherapy (NAC) [7,8]. There have been multiple reports that demonstrated better survival with less TILs in ER-positive BC, which is quite opposite to what is known in ER-negative tumors [9,10]
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