miR-378∗ Mediates Metabolic Shift in Breast Cancer Cells via the PGC-1β/ERRγ Transcriptional Pathway

SummaryCancer cell metabolism is often characterized by a shift from an oxidative to a glycolytic bioenergetics pathway, a phenomenon known as the Warburg effect. miR-378∗ is embedded within PPARGC1b which encodes PGC-1β, a transcriptional regulator of oxidative energy metabolism. Here we show that miR-378∗ expression is regulated by ERBB2 and induces a metabolic shift in breast cancer cells. miR-378∗ performs this function by inhibiting the expression of two PGC-1β partners, ERRγ and GABPA, leading to a reduction in tricarboxylic acid cycle gene expression and oxygen consumption as well as an increase in lactate production and in cell proliferation. In situ hybridization experiments show that miR-378∗ expression correlates with progression of human breast cancer. These results identify miR-378∗ as a molecular switch involved in the orchestration of the Warburg effect in breast cancer cells via interference with a well-integrated bioenergetics transcriptional pathway.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (210 K)Download as PowerPoint slideHighlights► miR-378∗ is embedded in the PGC-1β locus whose expression is modulated by ERBB2 ► miR-378∗ targets ERRγ and GABPA and modulates the expression of metabolic genes ► miR-378∗ induces the Warburg effect in mouse mammary and human breast cancer cells ► Expression of miR-378∗ correlates with progression of human breast cancer