Alayev Anya, Salamon Rachel S, Manna Subrata, Schwartz Naomi S, Berman Adi Y, Holz Marina K
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.
Cell Cycle. 2016 Dec;15(23):3230-3239. doi: 10.1080/15384101.2016.1241927. Epub 2016 Oct 18.
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.
同源重组（HR）是一种保守的过程，通过修复DNA双链断裂（DSB）来维持基因组稳定性和细胞存活。RAD51相关蛋白家族参与DSB的修复；因此，RAD51的失调会导致染色体重排并促进肿瘤发生。RAD51C已被确定为一种潜在的肿瘤抑制因子以及乳腺癌和卵巢癌易感基因。最近的研究还表明雌激素是一种导致DSB的DNA损伤剂。我们发现，在雌激素受体α（ERα）阳性的乳腺癌细胞中，雌激素通过ERα依赖机制转录调节RAD51C的表达。此外，雌激素诱导RAD51C在DSB处组装成核灶，这是RAD51复合物招募到细胞核的前体。此外，抗雌激素或小干扰RNA（siRNA）破坏ERα信号传导可阻止雌激素诱导的RAD51C上调。我们还发现RAD51C表达与肿瘤的ERα状态之间存在临床结果较差的关联。这些发现为ERα阳性乳腺癌的基因组不稳定机制提供了见解，并表明暴露于雌激素的RAD51C突变个体更容易积累DNA损伤，从而导致癌症进展。
