Oncotarget

Research Papers:

A recessive variant of XRCC4 predisposes to non- BRCA1/2 breast cancer in chinese women and impairs the DNA damage response via dysregulated nuclear localization

Min He, Xin Hu, Li Chen, A-Yong Cao, Ke-Da Yu, Ting-Yan Shi, Xia-Ying Kuang, Wen-Biao Shi, Hong Ling, Shan Li, Feng Qiao, Ling Yao, Qingyi Wei, Gen-Hong Di and Zhi-Ming Shao _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2014; 5:12218-12232. https://doi.org/10.18632/oncotarget.2623

Metrics: PDF 2582 views  |   HTML 2277 views  |   ?  


Abstract

Min He1,4, Xin Hu1, Li Chen1,4, A-Yong Cao1, Ke-Da Yu1, Ting-Yan Shi2, Xia-Ying Kuang1,4, Wen-Biao Shi1, Hong Ling1, Shan Li1, Feng Qiao1, Ling Yao1, Qingyi Wei3,5, Gen-Hong Di1,4 and Zhi-Ming Shao1,3,4

1 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China

2 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

3 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China

4 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

5 Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States of America

Correspondence:

Zhi-Ming Shao, email:

Xin Hu, email:

Keywords: XRCC4, homozygous variant, nuclear localization, susceptibility, breast cancer

Received: September 07, 2014 Accepted: October 22, 2014 Published: October 22, 2014

Abstract

XRCC4 plays a crucial role in the non-homologous end joining pathway that maintains genome stability. In this two-stage case-control study with 1,764 non-BRCA1/2 breast cancer patients and 1,623 cancer-free controls, we investigated the contribution of genetic variants of XRCC4 to breast cancer susceptibility in Chinese women. We identified a recessive missense variant, rs3734091 (c.739G>T, p.Ala247Ser), of XRCC4 that was significantly associated with an increased risk of breast cancer (odds ratio [OR] = 3.92, P = 0.007), particularly with the risk of developing triple-negative breast cancer (OR = 18.65, P < 0.0001). This p.Ala247Ser variant disturbed the nuclear localization of XRCC4 in cells homozygous for the rs3734091-T allele but not in heterozygous cells at both the cellular and tissue levels. In heterozygous cells, wild-type XRCC4 facilitated the nuclear localization of the XRCC4A247S mutant, thus compensating for the impaired localization of XRCC4A247S. This provided a biological mechanism by which rs3734091 conferred an increased susceptibility to non-BRCA1/2 breast cancer exclusively under a recessive model. Further functional analyses revealed that p.Ala247Ser impaired the DNA damage repair capacity and ultimately perturbed genomic stability. Taken together, our findings document the role of XRCC4 in non-BRCA1/2 breast cancer predisposition and reveal its underlying biological mechanism of action.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 2623