Basal-like subtype and BRCA1 dysfunction in breast cancers

Abstract

Basal-like breast cancers are characterized by their unique expression profile, with the frequent loss of BRCA1, caused by such mechanisms as promoter methylation and the overexpression of high-mobility group proteins of the A type 1 or inhibitor of differentiation 4. Clinicopathologically, basal-like cancers are estrogen receptor-, progesterone receptor-, and human epidermal growth factor receptor type 2 (HER2)-negative; they are of high grade and have a poor prognosis. The fundamental similarity between BRCA1-mutated and basal-like cancers indicates that disruption of BRCA1 may be an essential common initial pathogenic event. Furthermore, p53 mutation and EGFR overexpression occur similarly in BRCA1-mutated and basal-like cancers; these shared alterations provide very important information for understanding not only the genetic and epigenetic carcinogenic pathways in these tumors but also therapeutic strategies. Despite the limited available clinical data about response to chemotherapy, anthracycline-based chemotherapy seems to be effective in a distinct subset of basal-like cancers. Both disrupted BRCA1 and overexpressed topoisomerase II-alpha possibly found in basal-like cancers are speculated to be associated with their increased sensitivity to anthracyclines. If these tumors respond to this chemotherapy, a favorable prognosis might be expected; however, in patients who do not respond, the prognosis is poor. Currently, the sensitivity of basal-like cancers to taxanes is not clear, but considering that these tumors have disrupted mitotic checkpoint function, a poor response may be suggested. On the basis of in vitro studies, BRCA1-disrupted basal-like cancers may be sensitive to DNA-damaging agents including platinum-based compounds, topoisomerase I and II inhibitors, and alkylating agents. In future, new therapeutic approaches for patients with basal-like cancers that are unlikely to respond to chemotherapy should focus on molecules that are involved in the pathogenic pathways of this disease.

Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types

“…In normal tissues, PARP1 expression was generally low, with the exception of lymphoid tissues, which have increased frequency of recombination and genetic events during differentiation of B cells. 30 Due to previously reported observations of a role for PARP1 in the survival of BRCA1/2-deficient cells, 4,5 in addition to the high rates of BRCA1 mutations and/or dysfunction in TNBC, 10,11 we were particularly interested in comparing the levels of PARP1 expression in the available samples of breast IDC tissues, grouped according to the expression of ER, PR, and HER2. Importantly, negative expression of each receptor was associated with higher degrees of PARP1 upregulation, relative to receptor-positive counterparts of breast cancers evaluated.…”

“…Importantly, over 60% of sporadic cases of triple-negative breast cancer (TNBC) that are independent of BRCA1/2 germline mutations have been characterized by BRCA1 dysfunction due to promoter methylation or deregulation of other genes involved in transcriptional regulation. 10,11 Because low or negative expression of ER, PR, and HER2 precludes the use of currently available targeted therapies, development of novel targeted agents for TNBC represents a high priority for this patient population.…”

“…10,11 Due to observed associations between defects in DNA repair pathways and TNBC, 21,22 we hypothesized that these underlying defects could be linked and compensated by parallel DNA repair pathways. To investigate whether such a role existed for PARP1, we examined its expression levels within subpopulations of IDC, grouped according to expression of ER, PR, or HER2.…”

BRCA1 promoter methylation in peripheral blood cells is associated with increased risk of breast cancer with BRCA1 promoter methylation

“…Interestingly, phenotypes of breast tumors with BRCA1 promoter methylation, which lack expression of the BRCA1 protein due to BRCA1 gene silencing [19,20], are reported to be similar to those arising in patients with germline BRCA1 mutations in that they are more likely to be ER, PR [21][22][23], and HER2 negative tumors [24] as well as histologically high grade tumors [17]. These results seem to indicate that BRCA1 promoter methylation in sporadic breast tumors can be considered to occur relatively early in their pathogenesis.…”

Poly(ADP-Ribose) Polymerase-1 Inhibition: Preclinical and Clinical Development of Synthetic Lethality

“…The majority of BRCA1-defective breast tumors are estrogen-receptor and progesterone-receptor poor with no evidence of overexpression of Her2/neu. In addition, they exhibit a basal phenotype and poor prognosis (11).…”