Emerging roles of BRCA1 alternative splicing

Abstract

Germline mutations of the BRCA1 gene predispose individuals mainly to the development of breast and/or ovarian cancer. However, the exact function of the gene is still unclear, although the encoded proteins are involved in various cellular processes, including transcriptional regulation and DNA repair pathways. Several BRCA1 splice variants are found in different tissues, but in spite of intense investigations, their regulation and possible functions are poorly understood at the moment. This review summarises current knowledge on the roles of these splice variants and the mechanisms responsible for their formation. Because alternative splicing is now widely accepted as an important source of genetic diversity, elucidating the functions of the BRCA1 splice variants would help in the understanding of the exact role(s) of this tumour suppressor. This should help to resolve the current paradox that, despite its seemingly vital cellular functions, mutations of this gene are associated with tissue specific tumour formation predominantly in the breast and the ovary.

PIBF (progesterone induced blocking factor) is overexpressed in highly proliferating cells and associated with the centrosome

“…14 Alterations in the splicing pattern or splicing efficiency of several genes have been implicated in tumor progression (e.g., CD44, WT-1 and C-CAM1) and susceptibility to cancer (e.g., BRCA1). [15][16][17][18] In this study, we show a higher level of expression of the PIBF protein in breast tumors relative to normal breast tissue by immunohistochemistry. The TMA analysis suggested that at least 40% of breast tumors express a higher then normal level of PIBF.…”

“…17,18 One of the BRCA1 variants, deltaExon 11 missing two predicted nuclear localization signals was found to be localized in the cytoplasm, while the full-length protein was associated with the centrosome during mitosis and with the nucleus during interphase. 34,35 This is comparable to the predominant 35 kDa variant of PIBF that is also localized in the cytoplasm when it is overexpressed in HEK 293 cells and lacks the two predicted nuclear localization signals.…”

Identification of a novel splice variant of AML1b in ovarian cancer patients conferring loss of wild-type tumor suppressive functions

“…Herein, we show a marked accumulation of AML1 transcripts including a high frequency of a novel alternatively spliced AML1b transcript lacking exon 6 (AML1b Del179À242 ) in serous epithelial ovarian cancers suggesting that it may play an important role in ovarian tumorigenesis. Other proteins have been well documented to undergo alternative/aberrant splicing during cancer progression including mdm2 and BRCA1 (Bartel et al, 2002;Orban and Olah, 2003). Thus, deregulated splicing of oncogenes and tumor suppressors may be a common event during ovarian cancer progression.…”

Effectiveness and Safety of Poly (ADP-ribose) Polymerase Inhibitors in Cancer Therapy: A Systematic Review and Meta-analysis

“…There is no doubt that BRCA mutation made a major contribution to the improved results. Individuals with BRCA mutation are at an increased risk of developing breast, ovarian, and other cancers [34]. More than 1 million women develop breast or ovarian cancer every year worldwide, and about 10% of them have a BRCA mutation [35][36][37], moreover that cancer patients with BRCA mutation have better outcomes than non-BRCA carriers [38,39].…”