Abstract
Recent data have shown that the expression of lysosome-associated membrane protein type 2 A (LAMP2A), the key protein in the chaperone-mediated autophagy (CMA) pathway, is elevated in breast tumor tissues. However, the exact effects and mechanisms of CMA during breast cancer metastasis remain largely unknown. In this study, we found that the LAMP2A protein level was significantly elevated in human breast cancer tissues, particularly in metastatic carcinoma. The increased LAMP2A level was also positively correlated with the histologic grade of ductal breast cancer. High LAMP2A levels also predicted shorter overall survival of breast cancer patients. Downregulation of CMA activity by LAMP2A knockdown significantly inhibited the growth and metastasis of both MDA-MB-231 and MDA-MB-468 breast cancer cells in vivo and in vitro, while upregulation of CMA activity by LAMP2A overexpression had the opposite effect. Mechanistically, we found that elevated CMA activity mediated increased growth and metastasis of human breast cancer cells by downregulating the activity of autophagy-related gene 5 (ATG5)-dependent macroautophagy. Collectively, these results indicate that the anti-macroautophagic property is a key feature of CMA-mediated tumorigenesis and metastasis and may, in some contexts, serve as an attractive target for breast cancer therapies.
Highlights
Breast cancer is an important worldwide health problem
Given the evidence that the activity of the ATG5-ATG12 complex was upregulated in LAMP2A knockdown HeLa cells[17] and that macroautophagy serves as a pro-death mechanism in breast cancer cells[18,19,20], we hypothesized that the regulation of breast cancer cell metastasis by Chaperone-mediated autophagy (CMA) may be associated with ATG5-dependent macroautophagy
To determine whether CMA activity is increased in breast tumors or the related metastatic carcinoma in lymph nodes, we assessed LAMP2A expression in 166 breast cancer specimens and 21 normal breast epithelium specimens by immunohistochemical staining
Summary
Metastasis remains the primary cause of death for patients with breast cancer. Autophagy is a primary pathway by which intracellular components, such as proteins and organelles, are delivered to lysosomes and degraded, and this process plays a crucial role in tumor initiation and progression[3]. LAMP2A is the principal limiting component of the CMA pathway, as its protein levels at the lysosomal membrane directly determine CMA activity[7, 8]. The role of CMA activity in the malignant progression and metastasis of breast cancer remains largely unknown. To date, the interconnections between macroautophagy and CMA pathways in breast cancer cells remain unclear. Given the evidence that the activity of the ATG5-ATG12 complex was upregulated in LAMP2A knockdown HeLa cells[17] and that macroautophagy serves as a pro-death mechanism in breast cancer cells[18,19,20], we hypothesized that the regulation of breast cancer cell metastasis by CMA may be associated with ATG5-dependent macroautophagy
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