DMMC Course CANCER BIOLOGY TO CANCER MEDICINE

1450-1510 Thursday 25 May 2006.
Durkan Lecture Theatre, Institute of Molecular Medicine, TCD, St James's Hospital

BRCA1 signalling and cancer
Dr Paul Mullan (Centre for Cancer Research and Cell Biology, Queen's University Belfast)

BRCA1 was the first identified breast and ovarian cancer susceptibility gene, and was discovered in 1994. BRCA1 mutation carriers have recently been reported to have an 82% risk of developing breast cancer and a 54% risk of developing ovarian cancer by the age of 80. So it plays a major role in hereditary breast and ovarian cancers which constitute roughly 10% of cases for both cancer types. Recent publications now indicate that BRCA1 also plays a major role in the more common sporadic forms of both diseases (up to 30% and 70% of sporadic breast and ovarian cancers, respectively).

Although the exact function of BRCA1 remains to be defined, roles in DNA damage detection, DNA damage repair, cell cycle checkpoint control, transcriptional regulation and ubiquitination have been inferred. Much of the work performed on BRCA1 in Queens’ University Belfast focuses on the role of BRCA1 in transcriptional control. BRCA1 is thought to do this at multiple levels: by associating with the core transcriptional machinery (RNA polymerase II), with prominent transcription factors (STAT1, p53, and cmyc) and with proteins involved in chromatin remodeling (SWI-SNF complex).

Preclinical work from our group at QUB and numerous clinical studies have identified BRCA1 as being important in modulating the response to DNA damage chemotherapy. We have previously demonstrated that functional BRCA1 inhibits apoptosis in breast cancer cell lines following exposure to DNA-damaging chemotherapeutic agents. We observed that functional BRCA1 resulted in a significant (over 1000 fold) increase in resistance to the topoisomerase IIa poison, etoposide, when compared to BRCA1-deficient cells. In this lecture I will present data outlining possible signaling mechanisms of BRCA1 that may be involved in regulating cellular responses to DNA damage. Through a comparison of the expression profiles between the BRCA1-mutant HCC1937 cells reconstituted with functional BRCA1 and vector only reconstituted controls we have identified the S100A family of proteins as being etoposide inducible and potently repressed by BRCA1. We have demonstrated that BRCA1-dependent regulation of psoriasin (S100A7) is dependent on functional c-Myc and that psoriasin overexpression sensitises cells to etoposide. In addition I will discuss other aspects of BRCA1 function which contributes to its regulation of cell responses to chemotherapy.