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.
摘要：
三阴性乳腺癌（TNBC）组织的乳腺肿瘤起始细胞（BTIC）积极修复DNA，并且对包括化疗在内的治疗具有抗性，放射治疗,和靶向治疗。在这里，发现以前报道的分泌蛋白，硬化蛋白结构域含1（SOSTDC1），在TNBC细胞的BTIC中大量表达,并且与不良患者预后呈正相关。SOSTDC1敲低损害同源重组（HR）修复，BTIC维护,并使散装细胞和BTIC对Olaparib敏感。机械上,在Olaparib治疗之后，SOSTDC1以依赖输入蛋白-α的方式易位到细胞核。核SOSTDC1与核蛋白的N端相互作用，染色质解旋酶DNA结合因子（CHD1），促进HR维修和BTIC维护。此外，发现了与CHD1的β转导蛋白重复序列（β-TrCP）结合基序结合的核SOSTDC1，从而阻断β-TrCP-CHD1相互作用并抑制β-TrCP介导的CHD1泛素化和降解。总的来说，这些发现确定了在调节HR修复和BTIC维持中的新型核SOSTDC1途径，提供对TNBC治疗策略的见解。
