BRCA1 interactors and cancer

Felicity A Lose (2007). BRCA1 interactors and cancer PhD Thesis, School of Medicine, The University of Queensland.

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Author Felicity A Lose
Thesis Title BRCA1 interactors and cancer
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2007-05
Thesis type PhD Thesis
Supervisor Chenevix-Trench, Georgia
Khanna, Kumkum
Spurdle, Amanda B.
Subjects 320000 Medical and Health Sciences
Formatted abstract
Breast cancer affects more than 9% of the female Australian population and is the leading cause of mortality in females in most states. Hereditary breast cancer accounts for around 5-10% of all breast cancer cases, while the other 90-95% are assumed to be ‘sporadic’ (no apparent family history). It is well known that a proportion of familial breast cancer (around 25%) may involve mutations in the high-risk genes BRCA1 and BRCA2. Additional breast cancer genes have been discovered, largely through disease syndromes displaying a predisposition for breast cancer, however these are estimated to account for only a further 15% of familial breast cancer. Candidate genes for the remaining breast cancers include those that interact with BRCA1 since: 1) they are likely to be involved in some of the many important roles of BRCA1 such as genome maintenance and cell cycle regulation and, if mutated, may have the same highly penetrant and damaging effect as a BRCA1 mutation; 2) mutations in these interacting genes may prevent BRCA1 performing vital functions, resulting in the same acute effect as a BRCA1 mutation itself.
Human RAD51 is well known to be a central player in recombinational repair of double-stranded DNA breaks. Mutations in the lower eukaryotic homologues of RAD51 result in a deficiency in the repair of double-stranded DNA breaks. Loss of RAD51 function would therefore be expected to result in an elevated mutation rate, leading to accumulation of DNA damage and, hence, to increased cancer risk. RAD51 interacts directly or indirectly with a number of proteins implicated in breast cancer, such as BRCA1 and BRCA2. Few studies have investigated the role of coding region variation in the RAD51 gene in familial breast cancer to date. The RAD51 gene was screened for variation in 46 well-characterised, BRCA1/2-negative breast cancer families and lymphoblastoid cell lines (LCLs) from selected breast cancer patients were assessed for RAD51 expression changes. No coding region variation was found, and all intronic variation detected was either found in unaffected controls or was unlikely to have functional consequences. In addition, no allele-specific changes in RAD51 expression were detected in all lymphoblastoid cell lines tested. Our study indicates that RAD51 is not a major familial breast cancer predisposition gene.
BCoR-L1 (BCL6 corepressor-like 1) is a newly described BRCA1-interacting protein that displays high homology to several proteins known to be involved in the fundamental processes of DNA damage repair and transcription regulation. BCoR-L1 has been shown to play a role in transcription corepression, and the expression of the X-linked BCoR-L1 gene has been reported to be dysregulated in breast cancer subjects. We performed mutation analysis of 38 BRCA1/2 mutation¬negative breast cancer families to determine if there is a role for BCoR-L1 as a high-risk breast cancer predisposition gene. In addition, we conducted quantitative Real-Time PCR on LCLs from the index cases from these families and a number of cancer cell lines to assess the role of BCoR-L1 dysregulation in cancer. Very little variation was detected in the coding region and qRT-PCR analysis revealed that BCoR-L1 expression is highly variable in cancer-free subjects, high-risk breast cancer patients, and in cancer cell lines. We also report the investigation of a new expression control, DIDO1, that is superior to GAPD and UBC for analysis of expression in LCLs. Our results suggest that BCoR-L1 expression does not play a large role in predisposition to familial breast cancer.
Research into the X-linked BCoR-L1 gene and BRCA1 function continually highlighted the involvement of the X chromosome in breast and ovarian cancers. One particularly intriguing phenomenon apparently associated with risk of cancer was skewed X chromosome inactivation. X chromosome inactivation (XCI), the silencing of gene expression from one of the female X chromosomes, is a mechanism that has evolved in mammals to compensate for the fact that females carry double the complement of X chromosomes compared to males. Adult female tissues typically consist of an equal mixture of active paternal and maternal X chromosomes, in support of random
XCI. However, the silencing of the same X chromosome in most or all cells of a tissue (≥90%) has been observed (known as non-random or skewed XCI) and, importantly, occurs frequently in familial breast and population based-ovarian cancer cases. We assessed large, well-characterised breast and ovarian cancer sample populations, as well as a large control sample, for skewed XCI using an improved bisulfite modification technique. No significant association with skewed XCI was found in BRCA2 mutation carriers, BRCAX breast cancer patients and ovarian cancer cases. In contrast, BRCA1 carriers displayed a significantly increased frequency of skewed XCI, which, when stratified by breast cancer status (affected and unaffected), was highly significant in unaffected BRCA1 mutation carriers. Skewing was also associated with a significantly delayed age at onset of breast cancer. These results indicate the possibility of a risk modifier located on the X chromosome.

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Created: Thu, 29 May 2008, 13:10:51 EST by Noela Stallard on behalf of Library - Information Access Service