Abstract
This study investigated the network of genes that are co-expressed with androgen receptor (AR) to discover novel AR targets in breast cancer. Bioinformatics analysis of two datasets from breast cancer cell lines resulted in the identification of an AR-gene signature constituted of 98 genes that highly correlated with AR expression. Notably, C1orf64 showed the highest positive correlation with AR across the datasets with a correlation coefficient (CC) of 0.737. In addition, C1orf64 closely correlated with AR expression in primary and metastatic breast tumors and C1orf64 expression was relatively higher in breast tumors with a lower grade and lobular histology. Furthermore, there is a functional interplay between AR and C1orf64 in breast cancer. In this process, AR activation directly represses C1orf64 transcription and C1orf64, in turn, interacts with AR as a corepressor and negatively regulates the AR-mediated induction of prolactin-induced protein (PIP) and AR reporter activity. Moreover, the corepressor effect of C1orf64 results in a reduction of AR binding to PIP promoter. The other aspect of this interplay involves a cross-talk between AR and estrogen receptor (ER) signaling in which C1orf64 silencing intensifies the AR-mediated down-regulation of ER target gene, progesterone receptor. Therefore, the repression of C1orf64 by AR provides an underlying mechanism for the AR inhibitory effects on ER signaling. To elucidate the biochemical mechanisms of C1orf64 function, this study demonstrates that C1orf64 is a phosphothreonine protein that interacts with the chaperone protein 14-3-3. In summary, C1orf64 is a novel AR coregulator and a 14-3-3 binding partner in breast cancer.
Highlights
Recent advancements in the molecular profiling and cancer genomics have provided the opportunity for a better understanding of breast cancer biology and the discovery of novel therapeutic targets in this disease
Bioinformatics analysis of two datasets from breast cancer cell lines resulted in the identification of an ARgene signature constituted of 98 genes that highly correlated with androgen receptor (AR) expression
SPDEF showed a strong correlation with C1orf64 expression in this dataset with a CC of 0.573 (p≤ 0.0001, Figure 4B). These findings further prove that C1orf64 and AR are closely co-expressed across various subtypes and clinical stages of breast cancer with reproducible findings using different cohorts
Summary
Recent advancements in the molecular profiling and cancer genomics have provided the opportunity for a better understanding of breast cancer biology and the discovery of novel therapeutic targets in this disease. The subtype of ER-negative breast cancer that has a high level of AR expression is termed “molecular apocrine” and is characterized by a steroid-response gene signature that includes AR, FOXA1, and prolactin-induced protein (PIP), [5,6,7] These findings have resulted in a growing interest in the understanding of molecular functions and therapeutic implications of AR in breast cancer. Despite the emerging data on the importance of AR function in breast cancer, the available studies have been mostly conducted on a limited number of cell line models and broader molecular functions of AR in breast cancer including key targets and coregulators of this gene have remained largely unknown To address these shortcomings, my group has recently examined gene expression data from a cohort of 52 breast cancer cell lines to identify a network of AR co-expressed genes [20]. This study identifies a poorly-understood gene “C1orf64” as both a novel target gene and a coregulator of AR in breast cancer that interacts with 14-3-3 protein
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