BRCA1-induced Apoptosis Involves Inactivation of ERK1/2 Activities

Abstract

Breast cancer remains the most common cancer affecting women in the Western world. Although most breast cancers are sporadic, ϳ10% are inheritable and associated with mutations in at least two loci, BRCA1 and BRCA2. The BRCA1 gene is located at position 17q21 of the human genome, and mutations in this gene are associated with an increased risk of development of breast and ovarian cancer (1). The BRCA1 gene encodes a protein of 1864 amino acid residues that is primarily located in the nucleus (2). The BRCA1 gene product contains several domains that may effect its interaction with many other cellular proteins. The N terminus includes a domain presumably involved in the formation of homodimers and heterodimers (with the BARD1 protein) and a ring finger domain that is involved in interaction with BAP1 and E2F-1; the middle portion of BRCA1 contains a nuclear localization signal and domains that can bind to c-Myc, p53, pRB, and the DNA repair proteins RAD50 and RAD51; the C terminus includes two BRCT domains that interact with multiple factors involved in transcriptional regulation, including CtIP, p300, p53, pRB, CBP, BRCA2, RNA polymerase II, and RNA helicase A (3, 4). Recent studies suggest that the BRCA1 protein may be involved in regulating numerous cellular functions including DNA damage repair, gene transcription, chromosome segregation, cell cycle arrest, and apoptosis (4).Several studies suggest a role for BRCA1 in DNA repair. First, BRCA1 interacts with RAD51, a human homologue of the yeast RecA protein involved in double-stranded DNA break repair (5, 6). In vitro, BRCA1 can associate with the RAD50-MRE11-NBS1 complex, a functional unit implicated in homologous recombination, non-homologous end joining, and meiotic recombination. In irradiated cells, BRCA1 is recruited to this complex, where it likely plays a role in DNA repair (7). Moreover, ectopic expression of BRCA1 decreases cellular sensitivity to radiation and increases the efficiency of DNA break repair (8). Second, BRCA1 interacts with proteins involved in mismatch repair, mainly MSH2, MSH3, and MSH6. Furthermore, the association of BRCA1 with MSH2 and MSH6 was found to be essential for transcription-coupled DNA repair (9). A recent study by Wang et al. (9) provides evidence for the existence of a large BRCA1-containing complex that incorporates factors involved in various types of DNA repair. The identified complex was found to contain BRCA1 and the DNA repair factors MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11, NBS1, and replication factor C (9). These results suggest that BRCA1 might provide a scaffold that functions in coordinating multiple activities required for the maintenance of genomic integrity and the fidelity of DNA replication (9).Besides DNA repair function, numerous studies also suggest that BRCA1 might play an important role in transcriptional regulation. BRCA1 physically interacts with key enzymes involved in transcription, mainly RNA polymerase II and RNA helicase A, suggesting that it might be a component of the transcriptional ma...

MUC1 overexpression results in mammary gland tumorigenesis and prolonged alveolar differentiation

“…The specific downstream effects of Erk1 and Erk2 activation in the mammary epithelial cells are still not defined. However, a recent report indicates that inhibition of Erk1 and Erk2 activation results in increased apoptosis after BRCA1 expression in MCF-7 breast cancer cells (Yan et al, 2002). This suggests that the increases in Erk1 and Erk2 activation associated with MUC1 overexpression could provide a mechanism for the failure to eliminate cells by apoptosis, resulting in premalignant hyperplasia that contributes to mammary tumors.…”

BRCA1 gene in breast cancer

“…The increased susceptibility to apoptosis may be due, in part, to BRCA1-induced down-regulation of Bcl-2 and the transcriptional co-factor (p300) (Fan et al, 1998b(Fan et al, , 2001c, up-regulation of a Gadd45/JNK signaling pathway (Harkin et al, 1999), and up-regulation of the FasL/ Fas interaction (Yan et al, 2002). BRCA1-mediated apoptosis is also negatively regulated by activation of the ERK1/2 pathway (Yan et al, 2002). The dual roles of BRCA1 in DNA damage repair and apoptosis may be reconciled by postulating a ''caretaker'' function, in which BRCA1 mediates DNA damage signaling/repair when possible, but pushes cells into apoptosis when the damage is too great to repair.…”

ZBP-89-induced apoptosis is p53-independent and requires JNK

“…Similar to our findings with ZBP-89, overexpression of BRCA1 in MCF-7 breast cancer cells also activates both JNK (proapoptotic) and ERK (antiapoptotic) pathways, and MEK1/2 inhibition enhances BRCA1-induced apoptosis. 53 In fact, recent microarray analysis of MCF-7 cell line have revealed that ZBP-89 increases two-fold with overexpression of BRCA-1, suggesting that ZBP-89 lies downstream of this tumor suppressor gene product. 3 Thus, there may be synergy between BRCA1 and ZBP-89 apoptotic pathways.…”