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Review
. 2012 Nov 14;13(11):14898-916.
doi: 10.3390/ijms131114898.

A DNA repair BRCA1 estrogen receptor and _targeted therapy in breast cancer

Adisorn Ratanaphan  1
Affiliations
Review

A DNA repair BRCA1 estrogen receptor and _targeted therapy in breast cancer

Adisorn Ratanaphan. Int J Mol Sci. .

Abstract

BRCA1 is a key mediator of DNA repair pathways and participates in the maintenance of the genomic integrity of cells. The control of DNA damage repair mechanisms by BRCA1 is of great interest since molecular defects in this pathway may reflect a predictive value in terms of a cell's sensitivity to DNA damaging agents or anticancer drugs. BRCA1 has been found to exhibit a hormone-dependent pattern of expression in breast cells. Wild-type BRCA1 is required for the inhibition of the growth of breast tumor cells in response to the pure steroidal ERα antagonist fulvestrant. Also a loss of BRCA1-mediated transcriptional activation of ERα expression results in increased resistance to ERα antagonists. Platinum-based drugs, poly(ADP-ribose) polymerase (PARP) inhibitors, and their combination are currently included in chemotherapy regimens for breast cancer. Preclinical and clinical studies in a BRCA1-defective setting have recently indicated a rationale for the use of these compounds against hereditary breast cancers. Initial findings indicate that neoadjuvant use of cisplatin results in high rates of complete pathological response in patients with breast cancer who have BRCA1 mutations. Cisplatin produces a better response in triple-negative breast cancer (TNBC) than in non-TNBC diseases in both the neoadjuvant and adjuvant settings. This implies that TNBC cells may harbor a dysfunctional BRCA1 repair pathway.

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Figures

Figure 1
Figure 1
BRCA1 interacting proteins.
Figure 2
Figure 2
BRCA1-mediated homologous recombination (HR) repair. DNA double-strand break (the most destructive and cytotoxic DNA lesion is induced by irradiation or anticancer agents) activates the protein kinase ATM. The MRE11-RAD50-NSB1 (MRN) complex acts as a DSB sensor, recognizes DSB, and recruits ATM to the site of the DNA damage. ATM phophorylates the histone variant H2AX (γ-H2AX) that can directly recruit MDC1. ATM further phosphorylates MDC1, then recruits an E3 ubiquitin ligase, RNF8, that catalyzes polyubiquitin chains at the sites of DNA damage. The ubiquitin polymer next recruits the BRCA1-Abraxas-RAP80 complex through the RAP80 component. BRCA1 forms RING heterodimer E3 ligase activity with BARD1, which is required for recruitment of BRCA2 and RAD51 to damaged sites for HR repair through sister chromatid exchange. Resolvases restore Holliday junctions, and error-free DNA molecules are finally produced.
Figure 3
Figure 3
The functional domain of ERα.
Figure 4
Figure 4
The model for the mechanism of action of estrogen. An unoccupied estrogen receptor (ER) binds to HSP90 (I). Estrogen binds to the region E ligand binding domain (LBD). Antiestrogen tamoxifen is capable of inducing dimerization and DNA-binding, but does not activate the transcription-activation function 2 (TAF-2). ERE is an estrogen responsive DNA element.
Figure 5
Figure 5
Chemical structure of fulvestrant.
Figure 6
Figure 6
The molecular mechanism for the pure steroidal ERα antagonist, fulvestrant. Fulvestrant binds competitively to ERα with a high affinity. It acts as an antiestrogen chemical by reducing the half-life of ERα, resulting in a decrease in expression of ERα. Formation of the drug-receptor complex leads to stabilization of the receptor, which is degraded by an ubiquitin-proteasome complex.
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