Abstract
Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies.
Highlights
Androgen receptor (AR) signaling has become increasingly important in understanding the biology of breast cancer, and serves as a potential therapeutic target in the era of precision medicine.Previously, breast cancer has been categorized based on hormone receptor (HR) status, and the presence or absence of human epidermal growth factor 2 (HER2) amplification
The AR is a steroid-hormone activated transcription factor belonging to the nuclear receptor superfamily, a group that includes the estrogen receptor (ER) and progesterone receptor (PR)
Chromatin immunoprecipitation sequencing (ChIP-seq) and gene microarray analysis of the ZR-75-1 luminal breast cancer cell line identified that increased presence of one respective steroid hormone ligand (DHT versus estradiol) over the other leads to antagonism of the other pathway, at the level of transcription by binding to DNA response elements [40]
Summary
Androgen receptor (AR) signaling has become increasingly important in understanding the biology of breast cancer, and serves as a potential therapeutic target in the era of precision medicine. Breast cancer has been categorized based on hormone receptor (HR) status, and the presence or absence of human epidermal growth factor 2 (HER2) amplification. It has become apparent that the AR pathway is associated with breast tumor carcinogenesis, with differing mechanisms dependent on co-expression of HR or HER2 amplification [1,2] our understanding is still early, this signaling pathway has important prognostic and therapeutic implications. This review will aim to further clarify the complexities of the AR pathway in relation to breast cancer tumorigenesis, prognostic associations in relation to HR expression and HER2 amplification and potential therapeutic options
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