journal article·2024-08Open access

SOSTDC1 Nuclear Translocation Facilitates BTIC Maintenance and CHD1‐Mediated HR Repair to Promote Tumor Progression and Olaparib Resistance in TNBC

Qiaodan Deng, Jiankun Qiang, Cuicui Liu, Jiajun Ding, Juchuanli Tu, Xueyan He, Jie Xia, Xilei Peng, Siqin Li, Xian Chen, Wei Ma, Lu Zhang, Yi‐Zhou Jiang, Zhi‐Ming Shao, Ceshi Chen, Suling Liu, Jiahui Xu, Lixing Zhang

Advanced Science· Volume 11· Issue 29

Abstract

Abstract Breast tumor‐initiating cells (BTICs) of triple‐negative breast cancer (TNBC) tissues actively repair DNA and are resistant to treatments including chemotherapy, radiotherapy, and targeted therapy. Herein, it is found that a previously reported secreted protein, sclerostin domain containing 1 (SOSTDC1), is abundantly expressed in BTICs of TNBC cells and positively correlated with a poor patient prognosis. SOSTDC1 knockdown impairs homologous recombination (HR) repair, BTIC maintenance, and sensitized bulk cells and BTICs to Olaparib. Mechanistically, following Olaparib treatment, SOSTDC1 translocates to the nucleus in an importin‐α dependent manner. Nuclear SOSTDC1 interacts with the N‐terminus of the nucleoprotein, chromatin helicase DNA‐binding factor (CHD1), to promote HR repair and BTIC maintenance. Furthermore, nuclear SOSTDC1 bound to β‐transducin repeat‐containing protein (β‐TrCP) binding motifs of CHD1 is found, thereby blocking the β‐TrCP‐CHD1 interaction and inhibiting β‐TrCP‐mediated CHD1 ubiquitination and degradation. Collectively, these findings identify a novel nuclear SOSTDC1 pathway in regulating HR repair and BTIC maintenance, providing insight into the TNBC therapeutic strategies.
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Research context

OpenAlex topics: PARP inhibition in cancer therapy · DNA Repair Mechanisms · Cell death mechanisms and regulation

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences State Key Laboratory of Genetic Engineering Cancer Institutes Key Laboratory of Breast Cancer in Shanghai The Shanghai Key Laboratory of Medical Epigenetics Shanghai Key Laboratory of Radiation Oncology The International Co‐laboratory of Medical Epigenetics and Metabolism Ministry of Science and Technology Shanghai Medical College Fudan University Shanghai 200032 China

Research Center for Translational Medicine Shanghai East Hospital Tongji University School of Medicine Shanghai 200120 China

Department of Breast Surgery Shanghai Cancer Center and Cancer Institute Fudan University Shanghai 200032 P. R. China

Department of Thyroid Breast and Vascular Surgery Xijing Hospital The Fourth Military Medical University Xi'an 710032 P. R. China

Department of Breast Surgery Fudan University Shanghai Cancer Center Shanghai 200032 China

Key Laboratory of Breast Cancer in Shanghai Department of Oncology Shanghai Medical College Fudan University Shanghai 200032 China

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province Kunming Institute of Zoology Kunming 650201 China

Academy of Biomedical Engineering & The Third Affiliated Hospital Kunming Medical University Kunming 650118 China

Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Cancer Medicine Nanjing Medical University Nanjing 211166 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · Program of Shanghai Academic Research Leader

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