Breast cancer remains a significant health concern, with triple-negative breast cancer (TNBC) being an aggressive subtype with poor prognosis. Epithelial-mesenchymal transition (EMT) is important in early-stage tumor to invasive malignancy progression. Snail, a central EMT component, is tightly regulated and may be subjected to proteasomal degradation. We report a novel proteasomal independent pathway involving chaperone-mediated autophagy (CMA) in Snail degradation, mediated via its cytosolic interaction with HSC70 and lysosomal targeting, which prevented its accumulation in luminal-type breast cancer cells. Conversely, Snail predominantly localized to the nucleus, thus evading CMA-mediated degradation in TNBC cells. Starvation-induced CMA activation downregulated Snail in TNBC cells by promoting cytoplasmic translocation. Evasion of CMA-mediated Snail degradation induced EMT, and enhanced metastatic potential of luminal-type breast cancer cells. Our findings elucidate a previously unrecognized role of CMA in Snail regulation, highlight its significance in breast cancer, and provide a potential therapeutic target for clinical interventions.

中文翻译：

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伴侣介导的自噬调节 Snail 蛋白稳定性：对乳腺癌转移的影响


乳腺癌仍然是一个重大的健康问题，三阴性乳腺癌 （TNBC） 是一种预后不良的侵袭性亚型。上皮-间充质转化 （EMT） 在早期肿瘤向侵袭性恶性肿瘤进展中很重要。蜗牛是 EMT 的核心成分，受到严格调节，可能会受到蛋白酶体降解。我们报道了一种新的蛋白酶体非依赖性通路，涉及 Snail 降解中的伴侣介导的自噬 （CMA），通过其与 HSC70 的胞质相互作用和溶酶体靶向介导，从而阻止了其在管腔型乳腺癌细胞中的积累。相反，Snail 主要定位于细胞核，从而逃避 CMA 介导的 TNBC 细胞降解。饥饿诱导的 CMA 激活通过促进细胞质易位下调 TNBC 细胞中的 Snail。CMA 介导的 Snail 降解的逃避诱导了 EMT，并增强了管腔型乳腺癌细胞的转移潜力。我们的研究结果阐明了 CMA 在 Snail 调节中以前未被认识的作用，强调了它在乳腺癌中的重要性，并为临床干预提供了潜在的治疗靶点。