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

ABSTRACT: 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.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC10167262 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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

Zhu Ying Y Liu Zhixian Z Gui Liang L Yun Wen W Mao Changfei C Deng Rong R Yao Yufeng Y Yu Qiao Q Feng Jifeng J Ma Hongxia H Bao Wei W

NPJ breast cancer 20230508 1

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, w ...[more]

PMID: 37156759

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Project description:BackgroundDespite advancements in treatment approaches, patients diagnosed with aggressive breast cancer (BC) subtypes typically face an unfavorable prognosis. Globally, these cancers continue to pose a significant threat to women's health, leading to substantial morbidity and mortality. Consequently, there has been a significant struggle to identify viable molecular targets for therapeutic intervention in these patients. Polo-like Kinase-1 (PLK1) represents one of these molecular targets currently undergoing rigorous scrutiny for the treatment of such tumors. Yet, its role in the pathogenesis of BC in Middle Eastern ethnicity remains unexplored.MethodsWe investigated the expression of PLK1 protein in a cohort of more than 1500 Middle Eastern ethnicity BC cases by immunohistochemistry. Association with clinicopathological parameters and prognosis were performed. In vitro studies were conducted using the PLK1 inhibitor volasertib and the PARP inhibitor olaparib, either alone or in combination, in PTC cell lines.ResultsOverexpression of PLK1 was detected in 27.4% of all BC cases, and this was notably correlated with aggressive clinicopathological markers. PLK1 was enriched in the triple-negative breast cancer (TNBC) subtype and exhibited poor overall survival (p = 0.0347). Notably, there was a positive correlation between PLK1 and PARP overexpression, with co-expression of PLK1 and PARP observed in 15.7% of cases and was associated with significantly poorer overall survival (OS) compared to the overexpression of either protein alone (p = 0.0050). In vitro, we studied the effect of PLK1 and PARP inhibitors either single or combined treatments in two BRCA mutated, and one BRCA proficient TNBC cell lines. We showed that combined inhibition significantly reduced cell survival and persuaded apoptosis in TNBC cell lines. Moreover, our findings indicate that inhibition of PLK1 can reinstate sensitivity in PARP inhibitor (PARPi) resistant TNBC cell lines.ConclusionOur results shed light on the role of PLK1 in the pathogenesis and prognosis of Middle Eastern BC and support the potential clinical development of combined inhibition of PLK1 and PARP, a strategy that could potentially broaden the use of PLK1 and PARP inhibitors beyond BC cases lacking BRCA.

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

Publications

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

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