Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 44, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2109144118
Keywords
breast cancer stem cell; hypoxia-inducible factors; chemosensitivity; EMT
Categories
Funding
- National Natural Science Foundation of China [81702632]
- Natural Science Foundation of Shaanxi Province, China [2018JQ8004]
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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.
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