Abstract
PurposeAccumulating evidence has attracted attention to the androgen receptor (AR) as a biomarker and therapeutic target in breast cancer. We hypothesized that AR activity within the tumor has clinical implications and investigated whether androgen responsive serum factors might serve as a minimally invasive indicator of tumor AR activity.MethodsBased on a comprehensive gene expression analysis of an AR-positive, triple negative breast cancer patient-derived xenograft (PDX) model, 163 dihydrotestosterone (DHT)-responsive genes were defined as an androgen responsive gene set. Among them, we focused on genes that were DHT-responsive that encode secreted proteins, namely KLK3, AZGP1 and PIP, that encode the secreted factors prostate specific antigen (PSA), zinc-alpha-2-glycoprotein (ZAG) and prolactin induced protein (PIP), respectively. Using AR-positive breast cancer cell lines representing all breast cancer subtypes, expression of candidate factors was assessed in response to agonist DHT and antagonist enzalutamide. Gene set enrichment analysis (GSEA) was performed on publically available gene expression datasets from breast cancer patients to analyze the relationship between genes encoding the secreted factors and other androgen responsive gene sets in each breast cancer subtype.ResultsAnti-androgen treatment decreased proliferation in all cell lines tested representing various tumor subtypes. Expression of the secreted factors was regulated by AR activation in the majority of breast cancer cell lines. In GSEA, the candidate genes were positively correlated with an androgen responsive gene set across breast cancer subtypes.ConclusionKLK3, AZGP1 and PIP are AR regulated and reflect tumor AR activity. Further investigations are needed to examine the potential efficacy of these factors as serum biomarkers.
Highlights
Among women worldwide, breast cancer is the most frequently diagnosed cancer and one of the major causes of cancer-related mortality [1], and much more rare (< 1% of all breast cancer cases), it can afflict men as well [2]
We focused our study on three genes that were most highly upregulated following DHT treatment, Kallikrein related peptidase 3 (KLK3), Alpha2-Glycoprotein 1 (AZGP1) and PIP that encode the secreted proteins prostate specific antigen (PSA), zinc-Alpha-2-glycoprotein (ZAG) and prolactin induced protein (PIP) (Fig. 1b)
Gene expression of KLK3, AZGP1 and PIP is directly regulated by Androgen receptor (AR) in MDA‐MB‐453 cells MDA-MB-453 breast cancer cells highly express AR [43]
Summary
Breast cancer is the most frequently diagnosed cancer and one of the major causes of cancer-related mortality [1], and much more rare (< 1% of all breast cancer cases), it can afflict men as well [2]. AR plays a role in anchorage-independent cell survival and cancer stem cell-like characteristics including tumor initiation in-vivo [18,19,20,21,22] Based on these findings, both ongoing and completed clinical trials have been initiated to test the efficacy of AR-targeted therapies, such as bicalutamide and Enza, alone and in combination with other agents in both ER-positive and -negative breast cancer [15, 23]. There is no established predictive marker for response to AR-targeted therapy in breast cancer, Enza plus the aromatase inhibitor exemestane was shown to be effective in patients with ER-positive advanced breast cancers with a gene signature-based biomarker indicating AR activation [24], and both bicalutamide and enzalutamide showed efficacy in metastatic AR-positive triple-negative breast cancer (TNBC) [25, 26]. We explored candidate serum factors that reflect tumor AR activity to support development of noninvasive serum biomarkers of AR activity in breast cancer
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