Caveolin-1 inhibits breast cancer stem cells via c-Myc-mediated metabolic reprogramming

Shengqi Wang,Xu Chang,Bowen Yang,Fengxue Zhang,Zhiyu Wang,Neng Wang,Pengxi Liu,Yifeng Zheng,Min Li,Juxian Song

doi:10.1038/s41419-020-2667-x

Abstract

Breast cancer stem cells (BCSCs) are considered to be the root of breast cancer occurrence and progression. However, the characteristics and regulatory mechanisms of BCSCs metabolism have been poorly revealed, which hinders the development of metabolism-targeted treatment strategies for BCSCs elimination. Herein, we demonstrated that the downregulation of Caveolin-1 (Cav-1) usually occurred in BCSCs and was associated with a metabolic switch from mitochondrial respiration to aerobic glycolysis. Meanwhile, Cav-1 could inhibit the self-renewal capacity and aerobic glycolysis activity of BCSCs. Furthermore, Cav-1 loss was associated with accelerated mammary-ductal hyperplasia and mammary-tumor formation in transgenic mice, which was accompanied by enrichment and enhanced aerobic glycolysis activity of BCSCs. Mechanistically, Cav-1 could promote Von Hippel-Lindau (VHL)-mediated ubiquitination and degradation of c-Myc in BCSCs through the proteasome pathway. Notably, epithelial Cav-1 expression significantly correlated with a better overall survival and delayed onset age of breast cancer patients. Together, our work uncovers the characteristics and regulatory mechanisms of BCSCs metabolism and highlights Cav-1-targeted treatments as a promising strategy for BCSCs elimination.

Highlights

Breast cancer is the most commonly diagnosed malignancy (24.2% of new cancer diagnoses) and the leading cause of cancer-related deaths (15.0%) among women worldwide[1,2,3]
Considering that aerobic glycolysis is an essential characteristic of aggressive cancer cells that differs from normal cells[4], targeting aberrant glycolytic metabolism may be a promising strategy for cancer treatment
Breast cancer stem cells (BCSCs) isolated from mammary tumors of MMTV-Wnt[1] mice exhibited elevated glycolytic activity and decreased mitochondrial membrane potential when compared with normal breast stem cells (NBSCs) isolated from wild type mice, which was accompanied by decreased expression of Cav-1 but increased expression of c-Myc (Fig. 4d–f)

Summary

Introduction

Breast cancer is the most commonly diagnosed malignancy (24.2% of new cancer diagnoses) and the leading cause of cancer-related deaths (15.0%) among women worldwide[1,2,3]. The prevalence of breast cancer is still increasing globally every year, especially in young women[2]. It is of great urgency and clinical significance to identify novel antitumor strategies and targets for the prevention and treatment of breast cancer. Metabolic reprogramming is considered as one of the hallmarks of cancer[4]. Otto Warburg firstly observed that glucose uptake and lactate production were dramatically increased in cancer cells even in the presence of oxygen, which has been termed aerobic glycolysis[5]. Considering that aerobic glycolysis is an essential characteristic of aggressive cancer cells that differs from normal cells[4], targeting aberrant glycolytic metabolism may be a promising strategy for cancer treatment.

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Results

Conclusion