BRCA1 expression levels predict distant metastasis of sporadic breast cancers

Abstract

The role of BRCA1 in progression of sporadic breast cancers has to date been equivocal, although preliminary studies on small numbers of samples have suggested an association between expression levels of this gene and acquisition of an invasive phenotype. We have further reasoned that loss of oestrogen receptor positivity may have a detrimental effect on BRCA1 expression. In order to test this hypothesis and extend earlier investigations we have applied a sensitive RT-PCR procedure to determine the associations between BRCA1 expression and a variety of clinical parameters in a sample cohort derived from sporadic breast tumour specimens. We have established that BRCA1 and ER mRNA expression are closely associated (pϭ0.013), indicating a possible functional relationship between these 2 genes. We have further identified an association between low levels of BRCA1 expression and acquisition of distant metastasis in sporadic disease (pϭ0.019). In light of our findings, we suggest that suppression of BRCA1 has a role to play in progression of a significant fraction of sporadic breast cancers and may additionally prove to be a useful, novel, prognostic marker for this disease type. Int. J. Cancer (Pred. Oncol.) 84:258-262, 1999. Wiley-Liss, Inc.Breast cancer is one of the commonest malignancies in women, occurring in both hereditary and sporadic forms. About 5-10% of all cases are estimated to be familial. Of these, approximately 45% are attributable to germline mutations in one gene, BRCA1 (Miki et al., 1994;Easton et al., 1993Easton et al., , 1995. Mutations in BRCA1 also account for more than 75% of familial breast/ovarian cancers (Narod et al., 1995). In the breast, BRCA1 expression is specific to epithelial cells and is found at highest levels in terminal end buds during puberty and in developing alveoli during pregnancy (Marquis et al., 1995). Inhibition of BRCA1 expression leads to accelerated growth of both normal and malignant breast cancer cells (Thompson et al., 1995). Conversely overexpression of BRCA1 in breast cancer cell lines inhibits their growth in vitro and also inhibits their ability to form tumours in nude mice (Holt et al., 1996). In line with these observations, elevated expression of BRCA1, induced by retroviral infection of xenograft tumours, markedly improves long-term survival rates (Holt et al., 1996), suggesting that BRCA1 may function as a tumour suppressor. BRCA1 growth inhibition is cell-cycle dependent, and unlike other growth regulators such as p53 and pRb, is also cell-type specific (Holt et al., 1996). The cell specificity of BRCA1 growth inhibition suggests that analogues of this protein, or BRCA1-based gene therapy, may be of utility in treatment of sporadic as well as familial breast cancers (Holt et al., 1996). BRCA1 mRNA levels are indirectly elevated in breast cancer cells in response to oestrogen (Spillman and Bowcock, 1996;Marks et al., 1997) and a synergistic induction of BRCA1 expression is observed in ovariectomized mice treated with 17␤-oestradiol and progesterone (Marquis...

Quantitative Analysis of BRCA1 and BRCA2 mRNA Expression in Sporadic Breast Carcinomas and Its Relationship with Clinicopathological Characteristics

“…In order to clarify further the roles of BRCA1 and BRCA2 in breast carcinogenesis, the association of BRCA1 and BRCA2 mRNA expression with various clinicopathological factors of sporadic breast cancers needs to be studied. Although a few reports are available on this issue, 15,17) BRCA1 and BRCA2 mRNA expression levels were mostly examined by a semiquantitiatve reverse transcriptase-polymerase chain reaction (RT-PCR) assay, 15,17) and BRCA1 and BRCA2 mRNA expression levels were never examined together in these reports. Thus, in the present study, we have attempted to quantify both BRCA1 and BRCA2 mRNA levels with high accuracy, taking advantage of a real-time PCR, and to compare their expression levels with various clinicopathological factors in sporadic breast cancers.…”

Predictive and prognostic markers for invasive breast cancer

“…Previous studies have suggested that complete loss of the BRCA1 protein correlates with poor prognostic markers 55 and BRCA1 expression levels predict distant metastasis of sporadic breast cancers. 56 We further demonstrated that BRCA1 protein expression could provide an additional prognostic parameter for breast cancer. 18…”

Effect of 7-hydroxystaurosporine on glioblastoma cell invasion and migration1

“…BRCA1 (Breast Cancer susceptibility gene 1) is located at human chromosome 17q21, and mutations of BRCA1 are known to confer an added risk for breast and ovarian cancers in women, and for prostate cancer in men [22] . Increasingly, evidence indicates that invasive breast tumors show decreased BRCA1 mRNA expression and a loss of BRCA1 immunochemical staining relative to non-invasive tumors and benign tissues [23] . A clinical observation suggests that E-cadherin expression is potentially correlated with BRCA1-associated breast cancer [24] .…”