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Breast cancer is the second leading cause of cancer mortality in women after lung cancer. About 70% of breast cancers are positive for estrogen receptor alpha (ERα) at the time of diagnosis, and they respond well to anti-estrogen therapies; however, 40-50% of them become refractory over time. Thus, identifying novel therapeutic targets is critical to treat this ever-evolving disease. Recent studies suggest that the genes transcribed from chromosome X (X-linked genes) are implicated in several cancers. The expression of these genes is tightly regulated and restricted to immune-privileged organs; however, many of them escape regulation and are aberrantly expressed in tumors. Interestingly, our genomic analysis suggests that several of these genes are located at putative gene deserts in the human genome. To date, nothing is known about their expression and role in hormone-refractory breast cancer. In this regard, we used an integrated genomic approach to identify breast cancer-specific X-linked coding and noncoding genes. Furthermore, by combining gene expression analysis from MCF-7/TAMR-1 (tamoxifen resistant) breast cancer cells, we generated a comprehensive list of 100 estrogen-regulated, tamoxifen-resistant X-linked genes. Of 100 genes that met our stringent filtering criteria, 20 of them are long noncoding RNAs (lncRNAs), localize directly to chromatin and robustly regulated by estrogen. Each of these lncRNAs has a unique expression pattern in normal human tissues and breast cancer. For example, recently annotated primate-specific lncRNA1476 (a.k.a. UEBC - Upregulated in ER+ Breast Cancer), found in ovary, uterus, and fallopian tubes, and is localized to chromatin. The UEBC is regulated by estrogen and/or tamoxifen, and its expression predicts poor outcome in ERα+ breast cancer patients. UEBC has now been fully annotated (transcription start and stop site, 5’ cap, polyA tail, and exon/intron structure), and cloned. Gene expression combined with genome-wide analysis of ERα recruitment at enhancers indicate that UEBC plays a critical role in the estrogen-dependent transcription. Collectively, our results suggest that UEBC is an excellent target with prognostic and therapeutic potential in hormone-refractory breast cancer. Supported by a grant from the Cancer Prevention and Research Institute of Texas |
