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。上皮间质转化（EMT）对于早期肿瘤向侵袭性恶性肿瘤的进展非常重要。 Snail 是 EMT 的核心成分，受到严格调控，可能会受到蛋白酶体降解。我们报告了 Snail 降解中涉及伴侣介导的自噬 (CMA) 的一种新的蛋白酶体独立途径，通过其与 HSC70 的胞质相互作用和溶酶体靶向介导，从而阻止其在管腔型乳腺癌细胞中积累。相反，Snail 主要定位于细胞核，从而避免 TNBC 细胞中 CMA 介导的降解。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。逃避 CMA 介导的 Snail 降解可诱导 EMT，并增强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 调节中先前未被认识的作用，强调了其在乳腺癌中的重要性，并为临床干预提供了潜在的治疗靶标。© 2024。作者。

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.© 2024. The Author(s).