title: Estrogen induces RAD51C expression and localization to sites of DNA damage.
abstract: Homologous recombination (HR) is a conserved process that maintains genome stability and cell survival by repairing DNA double-strand breaks (DSBs). The RAD51-related family of proteins is involved in repair of DSBs; consequently, deregulation of RAD51 causes chromosomal rearrangements and stimulates tumorigenesis. RAD51C has been identified as a potential tumor suppressor and a breast and ovarian cancer susceptibility gene. Recent studies have also implicated estrogen as a DNA-damaging agent that causes DSBs. We found that in ERα-positive breast cancer cells, estrogen transcriptionally regulates RAD51C expression in ERα-dependent mechanism. Moreover, estrogen induces RAD51C assembly into nuclear foci at DSBs, which is a precursor to RAD51 complex recruitment to the nucleus. Additionally, disruption of ERα signaling by either anti-estrogens or siRNA prevented estrogen induced upregulation of RAD51C. We have also found an association of a worse clinical outcome between RAD51C expression and ERα status of tumors. These findings provide insight into the mechanism of genomic instability in ERα-positive breast cancer and suggest that individuals with mutations in RAD51C that are exposed to estrogen would be more susceptible to accumulation of DNA damage, leading to cancer progression.
authors.affiliation: a Department of Biology , Yeshiva University , New York , NY , USA.
authors.forename: Anya
authors.initials: A
authors.lastname: Alayev
authors.affiliation: a Department of Biology , Yeshiva University , New York , NY , USA.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Salamon
authors.affiliation: a Department of Biology , Yeshiva University , New York , NY , USA.
authors.forename: Subrata
authors.initials: S
authors.lastname: Manna
authors.affiliation: a Department of Biology , Yeshiva University , New York , NY , USA.
authors.forename: Naomi S
authors.initials: NS
authors.lastname: Schwartz
authors.affiliation: a Department of Biology , Yeshiva University , New York , NY , USA.
authors.forename: Adi Y
authors.initials: AY
authors.lastname: Berman
authors.affiliation: a Department of Biology , Yeshiva University , New York , NY , USA.|b Department of Molecular Pharmacology and the Albert Einstein Cancer Center , Albert Einstein College of Medicine , Bronx , NY , USA.
authors.forename: Marina K
authors.initials: MK
authors.lastname: Holz
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D030541:Databases, Genetic; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D021381:Protein Transport / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D004268:DNA-Binding Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; C448305:RAD51C protein, human
keywords: DNA double-strand break repair; ERα; RAD51C; breast cancer; estrogen