期刊
CELL DEATH & DISEASE
卷 12, 期 6, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-021-03781-x
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资金
- National Natural Science Foundation of China [81730074, 81672599, 82002781]
The study reveals that SGLT1 overexpression drives tamoxifen resistance in breast cancer cells by promoting M2-like TAM polarization through enhanced lactic acid secretion. M2-like TAMs activate breast cancer cells via signaling pathways, forming a vicious cycle of drug resistance.
Endocrine therapy is the standard treatment for estrogen receptor (ER)-positive breast cancer, but tumors eventually develop resistance. However, endocrine therapy resistance mechanisms mediated through interactions between breast cancer cells and tumor-associated macrophages (TAMs) are still unclear. Here, we characterized sodium/glucose cotransporter 1 (SGLT1) overexpression drives the highly glycolytic phenotype of tamoxifen-resistant breast cancer cells where enhanced lactic acid secretion promotes M2-like TAM polarization via the hypoxia-inducible factor-1 alpha/signal transducer and activator of transcription-3 pathway. In turn, M2-like TAMs activate breast cancer cells through EGFR/PI3K/Akt signaling, providing feedback to upregulate SGLT1 and promote tamoxifen resistance and accelerate tumor growth in vitro and in vivo. Higher expression of SGLT1 and CD163(+) TAMs was associated with endocrine-resistant ER-positive breast cancers. Our study identifies a novel vicious cycle of metabolic reprogramming, M2-like TAM polarization, and endocrine therapy resistance, which involves SGLT1, proposing SGLT1 as a therapeutic target to overcome endocrine therapy resistance in breast cancer.
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