2. Academic Validation
  3. Sodium/glucose cotransporter 1-dependent metabolic alterations induce tamoxifen resistance in breast cancer by promoting macrophage M2 polarization

Sodium/glucose cotransporter 1-dependent metabolic alterations induce tamoxifen resistance in breast cancer by promoting macrophage M2 polarization

  • Cell Death Dis. 2021 May 18;12(6):509. doi: 10.1038/s41419-021-03781-x.
Xingjian Niu  # 1,  Jianli Ma  # 2,  Jingtong Li 1,  Yucui Gu 1,  Lei Yin 3 4,  Yiran Wang 3 4,  Xiaoping Zhou 1,  Jinlu Wang 1,  Hongfei Ji 5 6,  Qingyuan Zhang 7 8 9
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, 150081, Heilongjiang, China.
  • 2 Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, Heilongjiang, China.
  • 3 Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin, 150081, Heilongjiang, China.
  • 4 Heilongjiang Academy of Medical Sciences, Harbin, 150081, Heilongjiang, China.
  • 5 Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin, 150081, Heilongjiang, China. jihongfei@hrbmu.edu.cn.
  • 6 Heilongjiang Academy of Medical Sciences, Harbin, 150081, Heilongjiang, China. jihongfei@hrbmu.edu.cn.
  • 7 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, 150081, Heilongjiang, China. zqyHMU1965@163.com.
  • 8 Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin, 150081, Heilongjiang, China. zqyHMU1965@163.com.
  • 9 Heilongjiang Academy of Medical Sciences, Harbin, 150081, Heilongjiang, China. zqyHMU1965@163.com.
  • # Contributed equally.
PMID: 34006822 DOI: 10.1038/s41419-021-03781-x
Abstract

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-1α/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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