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 stromal invasion of breast cancer cells. Here we show that LAMA5, a central BM component, is critical for luminal mammary tumour initiation, and controls tumor progression and phenotype development. LAMA5 is overexpressed in both human and mouse luminal mammary tumours 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 from mature hormone receptor (HR+) positive luminal epithelial phenotype towards a HR+ progenitor phenotype, and widespread alterations in extracellular matrix and Fibroblast growth factor (Fgf) signalling genes, including overexpression of Fgf receptor 2 (Fgfr2) in the HR+ progenitor cells. Single allele deletion, but not biallelic deletion of Lama5 additionally inhibits growth and progression towards advanced mammary carcinomas. However, inhibition of Fgf receptors restores growth decrease and induces apoptosis in biallelic- Lama5- deleted organoids without affecting wildtype organoids. Our analyses demonstrate a critical role for a BM component LAMA5 in mammary tumour initiation and reveal mechanisms of extracellular matrix-epithelial interplay in breast tumour progression and phenotype maintenance.