Type IV collagen α5 chain promotes luminal breast cancer progression through c-Myc-driven glycolysis

Cancer cell metabolism reprogramming is one of the hallmarks of cancer. Cancer cells preferentially utilize aerobic glycolysis, which is regulated by activated oncogenes and the tumor microenvironment. Extracellular matrix (ECM) in the tumor microenvironment, including the basement membranes (BMs), is dynamically remodeled. However, whether and how ECM regulates tumor glycolysis is largely unknown. We show that type IV collagens, components of BMs essential for the tissue integrity and proper function, are differentially expressed in breast cancer subtypes that alpha 5 chain (alpha 5(IV)) is preferentially expressed in the luminal-type breast cancer and is regulated by estrogen receptor-alpha. alpha 5(IV) is indispensable for luminal breast cancer development. Ablation of alpha 5(IV) significantly reduces the growth of luminal-type breast cancer cells and impedes the development of luminal-type breast cancer. Impaired cell growth and tumor development capability of alpha 5(IV)-ablated luminal breast cancer cells is attributed to the reduced expression of glucose transporter and glycolytic enzymes and impaired glycolysis in luminal breast cancer cells. Non-integrin collagen receptor discoidin domain receptor-1 (DDR1) expression and p38 mitogen-activated protein kinase activation are attenuated in alpha 5(IV)-ablated luminal breast cancer cells, resulting in reduced c-Myc oncogene expression and phosphorylation. Ectopic expression of constitutively active DDR1 or c-Myc restores the expression of glucose transporter and glycolytic enzymes, and thereafter restores aerobic glycolysis, cell proliferation, and tumor growth of luminal breast cancer. Thus, type IV collagen alpha 5 chain is a luminal-type breast cancer-specific microenvironmental regulator modulating cancer cell metabolism.

Automated summary

Reprogramming of cancer cell metabolism, particularly through the preference for aerobic glycolysis, plays a critical role in cancer development. The extracellular matrix (ECM), including basement membranes (BMs), in the tumor microenvironment, regulates tumor glycolysis. This study reveals that alpha 5 chain of type IV collagen is a specific microenvironmental regulator in luminal-type breast cancer, modulating cancer cell metabolism and tumor development.