Cell lines:
- BRCA has been detected in several breast cancer cell (BCC) lines including MCF-7, MDA-MB-231, MDA-MB-435, BT-20.
- BRCA1 expression is regulated by estrogens in human BCC lines (Spillman M.A. and Bowcock A.M., 1996).
- Overexpression of BRCA1 in BCC lines inhibits their growth in vitro and also inhibits their ability to form tumors in nude mice (Holt J.T. et al., 1996).
- In transient transfection assays in T-47D, MCF-7, and MDA-MB-231 BCC, BRCA1 was found to inhibit signaling by the ligand-activated
estrogen receptor-alpha through the estrogen-responsive enhancer element and to block the transcriptional activation function AF2 of
ER-alpha. This raises the possibility that wild-type BRCA1 suppresses estrogen-dependent transcriptional pathways related to mammary epithelial cell proliferation and that loss of this ability contributes to tumorigenesis (Fan S. et al., 1999).
Tumors:
- The BRCA1 gene is frequently mutated in families at high risk of developing breast cancer. About 5-10% of all breast cancer cases are estimated to be familial. Of these, approximately 45% are attributable to germline mutations of BRCA1. More than 500 different mutations or polymorphisms in the BRCA1 gene have been described. In most cases, these modifications lead to the incomplete translation of the BRCA1 mRNA.
- In sporadic breast cancer, BRCA1 mRNA levels are markedly decreased during the transition from carcinoma in situ to invasive cancer. Inhibition of BRCA1 expression with antisense oligonucleotides produced accelerated growth of normal and malignant mammary cells but had no effect on nonmammary epithelial cells. Thus, BRCA1 could normally serve as a negative regulator of mammary epithelial cell growth and this function could be compromised in breast cancer either by direct mutation or by alterations in gene expression (Thompson et al., 1995).
-
Progesterone receptor and
cyclin D expression was found lower in BRCA1 and
BRCA2-associated (familial) breast cancers than in sporadic cancers. No difference was found for the
estrogen receptor and
pS2 (Osin P. et al., 1998).
- Elevated expression of BRCA1, induced by retroviral infection of xenograft tumors, markedly improves long-term survival rates in mice (Holt J.T. et al., 1996).
- Hypermethylation of the BRCA1 promoter region has been reported in sporadic breast tumour samples, although this does not appear to be a common mechanism for BRCA1 repression (Dobrovic A. and Simpfendorfer D., 1997).
- It has been suggested that aberrant cytosine methylation of the BRCA1 CpG island promoter may be one mechanism of BRCA1 repression in sporadic breast cancer (Rice J.C. et al., 1998).
- BRCA1 mRNA levels were found to be significantly lower in sporadic breast cancers (37 cases analysed, 24 cases of invasive ductal carcinomas not otherwise specified (NOS), two lobular carcinomas in situ two medullary carcinomas, four invasive lobular carcinomas, two invasive mucinous carcinomas and three invasive ductal carcinomas with predominantly
in situ component) compared with normal breast tissues (P=0.0003). This down-regulation of BRCA1 was observed in all histologic types analysed. In invasive ductal carcinomas NOS, this down-regulation did not correlate with any of the prognostic factors studied (tumor size, node status, histologic grade, hormone receptor status). In the samples analysed, alterations of DNA methylation patterns were not dectected in the vicinity of the major transcription start site (Magdinier F. et al., 1998).
- Loss of heterozygosity (LOH) was found in the BRCA1 region in 53/107 (49%) breast tumors. LOH in this region was significantly correlated to age <=50, lymph node metastase >3,
estrogen receptor negativity,
progesterone receptor negativity, higher histologic grade, higher stage, and peritumoral vessel involvement (Gonzalez R. et al., 1999).
- BRCA1 and
BRCA2 are expressed in milk fat globules, suggesting a possible role of these proteins in lactation (Bernard-Gallon D.J. et al., 1999).
- By immunohistochemistry, discrete nuclear foci of BRCA1 proteins were found in benign breast, invasive lobular cancers, and low-grade ductal carcinomas. Conversely, BRCA1 expression was reduced or undetectable in the majority of high-grade, ductal carcinomas, suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers (Wilson C.A. et al., 1999). One possible explanation for the absence of BRCA-1 expression in sporadic cancers could be gene methylation (Mancini D.N. et al., 1997).
- In a series of 53 sporadic breast tumors, BRCA1 and ER mRNA expression were closely associated (p=0.013), indicating a possible functional relationship between these 2 genes. Moreover, an association was found between low levels of BRCA1 expression and acquisition distant metastasis in sporadic disease (p=0.019) (Seery L.T. et al. 1999).
- BAP1 is a nuclear-localized, ubiquitin carboxy-terminal hydrolase able to bind to BRCA1-RING finger domain and to enhance BRCA1-mediated inhibition of breast cancer cell growth. BAP1 might be a tumor suppressor gene which functions in the BRCA1 growth control pathway (Jensen D.E. et al., 1998).
Bernard-Gallon D.J. et al. (1999) BRCA1 and
BRCA2 proteins are expressed in milk fat globules. Int. J. Cancer 81, 839-843.
Chen J. et al. (1998) Stable interaction between the products of the BRCA1 and
BRCA2 tumor suppressor genes in mitotic and meiotic cells. Molec. Cell 2, 317-328.
Chen Y. et al. (1996) BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner. Cancer Res. 56, 3168-3172.
Dobrovic A. and Simpfendorfer D. (1997) Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res. 57, 3347-3350.
Fan S. et al. (1999) BRCA1 inhibition of
estrogen receptor signaling in transfected cells. Science 284, 1354-1356.
Gonzales R. et al. (1999) Detection of loss of heterozygosity at RAD51, RAD52, RAD54 and BRCA1 and
BRCA2 loci in breast cancer: pathological correlations. Br. J. Cancer 81, 503-509.
Holt J.T. et al. (1996) Growth retardation and tumor inhibition by BRCA1. Nature Genet. 12, 298-302.
Jensen D.E. et al. (1998) BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16, 1097-1112.
Magdinier F. et al. (1998) Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region. Oncogene 17, 3169-3176.
Mancini D.N. et al. (1997) Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res. 57, 3347-3350.
Miki Y. et al. (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA-1. Science 266, 66-71.
Osin P. et al. (1998) Predicted anti-oestrogen resistance in
BRCA-associated familial breast cancers. Eur. J. Cancer 34, 1683-1686.
Rice J.C. et al. (1998) Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. Oncogene 17, 1807-1812.
Ruffner H. and Verma I.M. (1997) BRCA1 is a cell cycle-regulated nuclear phosphoprotein. Proc. Natl. Acad. Sci. USA 94, 7138-7143.
Scully R. et al. (1997) BRCA1 is a component of the RNA polymerase II holoenzyme. Proc. Nat. Acad. Sci. 94, 5605-5610.
Seery L.T. et al. (1999) BRCA1 expression levels predict distant metastasis of sporadic breast cancers. Int. J. Cancer 84, 258-262.
Spillman M.A. and Bowcock A.M. (1996) BRCA1 and
BRCA2 mRNA are coordinately elevated in human breast cancer cells in response to estrogen. Oncogene 13, 1639-1645.
Thompson M.E. et al. (1995) Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nature Genet. 9, 444-450.
Wilson C.A. et al. (1999) Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nature Genet. 21, 236-240.
