Tumour-derived LAMA5 is critical for tumour initiation and controls progression and phenotype in luminal breast cancer

Abstract

Basement membrane (BM) supports and regulates the structural integrity, function and differentiation of epithelial tissues and protects against breast cancer invasion to stroma. Here we show that the BM component LAMA5 is critical for initiation of luminal mammary tumours, and controls tumour progression and phenotype development. LAMA5 is overexpressed in human breast carcinomas and LAMA5 downregulation attenuates growth of human breast cancer cells. Prepubertal luminal deletion of Lama5 in MMTV-PyMT mice results in marked reduction in emergence of early hyperplasias, along with a shift towards luminal progenitor-like phenotype. However, single allele deletion, but not biallelic deletion of Lama5 inhibits growth and progression towards advanced mammary carcinomas. Lama5 deficient luminal epithelial cells collectively display widespread alterations in Fibroblast growth factor (Fgf) signalling genes, including increased expression of Fgf receptor 2 (Fgfr2). Inhibition of Fgf receptors decreases growth and induces apoptosis also in biallelic-Lama5-deleted organoids without affecting wildtype organoids. Our results demonstrate a critical role for the BM component LAMA5 in mammary tumour initiation and reveal mechanisms of ECM-epithelial interplay in breast tumour progression and phenotype maintenance.