期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2109144118
关键词
breast cancer stem cell; hypoxia-inducible factors; chemosensitivity; EMT
资金
- National Natural Science Foundation of China [81702632]
- Natural Science Foundation of Shaanxi Province, China [2018JQ8004]
CALR is overexpressed in breast cancer and correlates with patient mortality and stemness indices. It promotes breast cancer stem cell formation and progression through Wnt/beta-catenin signaling in an HIF-1-dependent manner. These findings suggest CALR may be a potential target for breast cancer therapy.
Calreticulin (CALR) is a multifunctional protein that participates in various cellular processes, which include calcium homeostasis, cell adhesion, protein folding, and cancer progression. However, the role of CALR in breast cancer (BC) is unclear. Here, we report that CALR is overexpressed in BC compared with normal tissue, and its expression is correlated with patient mortality and stemness indices. CALR expression was increased in mammosphere cultures, CD24-CD44+ cells, and aldehyde dehydrogenase-expressing cells, which are enriched for breast cancer stem cells (BCSCs). Additionally, CALR knockdown led to BCSC depletion, which impaired tumor initiation and metastasis and enhanced chemosensitivity in vivo. Chromatin immunoprecipitation and reporter assays revealed that hypoxia-inducible factor 1 (HIF-1) directly activated CALR transcription in hypoxic BC cells. CALR expression was correlated with Wnt/ beta-catenin pathway activation, and an activator of Wnt/beta-catenin signaling abrogated the inhibitory effect of CALR knockdown on mammosphere formation. Taken together, our results demonstrate that CALR facilitates BC progression by promoting the BCSC phenotype through Wnt/beta-catenin signaling in an HIF-1-dependent manner and suggest that CALR may represent a target for BC therapy.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据