Inhibition of CXorf56 promotes PARP inhibitor-induced cytotoxicity in triple-negative breast cancer

被引：3

作者：

Zhu, Ying ^{[1
,2
,3
]}

Liu, Zhixian ^{[2
,3
,4
]}

Gui, Liang ^{[1
,2
,3
]}

Yun, Wen ^{[1
,2
,3
]}

Mao, Changfei ^{[1
,2
,3
]}

Deng, Rong ^{[1
,2
,3
]}

Yao, Yufeng ^{[1
,2
,3
]}

Yu, Qiao ^{[1
,2
,3
]}

Feng, Jifeng ^{[1
,2
,3
]}

Ma, Hongxia ^{[5
]}

Bao, Wei ^{[6
]}

机构：

[1] Nanjing Med Univ, Dept Gen Surg, Jiangsu Canc Hosp, Nanjing, Peoples R China

[2] Nanjing Med Univ, Jiangsu Inst Canc Res, Nanjing, Peoples R China

[3] Nanjing Med Univ, Affiliated Canc Hosp, Nanjing, Peoples R China

[4] Nanjing Med Univ, Dept Pharm, Jiangsu Canc Hosp, Nanjing, Peoples R China

[5] Nanjing Med Univ, Dept Epidemiol, Ctr Global Hlth, Sch Publ Hlth,Jiangsu Key Lab Canc Biomarkers Prev, Nanjing, Peoples R China

[6] Nanjing Univ, Jinling Hosp, Affiliated Hosp, Dept Pathol,Med Sch, Nanjing, Peoples R China

来源：

NPJ BREAST CANCER | 2023年 / 9卷 / 01期

基金：

中国博士后科学基金;

关键词：

HOMOLOGOUS RECOMBINATION; DNA-REPAIR; HEPATOCELLULAR-CARCINOMA; SYNTHETICALLY LETHAL; RAD52; INACTIVATION; BRCA MUTATION; DEFICIENCY; POLY(ADP-RIBOSE); MORTALITY; MECHANISM;

D O I：

10.1038/s41523-023-00540-3

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Poly(ADP-ribose) polymerase inhibitors (PARPis) induce DNA lesions that preferentially kill homologous recombination (HR)-deficient breast cancers induced by BRCA mutations, which exhibit a low incidence in breast cancer, thereby limiting the benefits of PARPis. Additionally, breast cancer cells, particularly triple-negative breast cancer (TNBC) cells, exhibit HR and PARPi resistance. Therefore, targets must be identified for inducing HR deficiency and sensitizing cancer cells to PARPis. Here, we reveal that CXorf56 protein increased HR repair in TNBC cells by interacting with the Ku70 DNA-binding domain, reducing Ku70 recruitment and promoting RPA32, BRCA2, and RAD51 recruitment to sites of DNA damage. Knockdown of CXorf56 protein suppressed HR in TNBC cells, specifically during the S and G2 phases, and increased cell sensitivity to olaparib in vitro and in vivo. Clinically, CXorf56 protein was upregulated in TNBC tissues and associated with aggressive clinicopathological characteristics and poor survival. All these findings indicate that treatment designed to inhibit CXorf56 protein in TNBC combined with PARPis may overcome drug resistance and expand the application of PARPis to patients with non-BRCA mutantion.

引用

页数：13