TGF beta induces the formation of tumour-initiatingcells in claudin low breast cancer

摘要

The role of transforming growth factor-beta (TGF beta) in the progression of different molecularsubtypes of breast cancer has not been clarified. Here we show that TGF beta increases breasttumour-initiating cell (BTIC) numbers but only in claudinlow breast cancer cell lines by orchestrating a specific gene signature enriched in stem cell processes that predicts worseclinical outcome in breast cancer patients. nEDD9, a member of the Cas family of integrinscaffold proteins, is necessary to mediate these TGF beta-specific effects through a positivefeedback loop that integrates TGF beta/smad and Rho-actin-sRF-dependent signals. In normalhuman mammary epithelium, TGF beta induces progenitor activity only in the basal/stem cellcompartment, where claudinlow cancers are presumed to arise. These data show opposingresponses to TGF beta in both breast malignant cell subtypes and normal mammary epithelial cellsubpopulations and suggest therapeutic strategies for a subset of human breast cancers.