The role of fibroblast growth factor receptor 2 (FGFR2), an important mediator of stromal paracrine and autocrine signals, in mammary gland morphogenesis and breast cancer has been extensively studied over the last years. However, the function of FGFR2 signalling in the initiation of mammary epithelial oncogenic transformation remains elusive. Here, FGFR2-dependent behaviour of nontumorigenic model of mammary epithelial cells was studied. In vitro analyses demonstrated that FGFR2 regulates epithelial cell communication with extracellular matrix (ECM) proteins. Silencing of FGFR2 significantly changed the phenotype of cell colonies in three-dimensional cultures, decreased integrins α2, α5 and β1 protein levels and affected integrin-driven processes, such as cell adhesion and migration. More detailed analysis revealed the FGFR2 knock-down-induced proteasomal degradation of integrin β1. Analysis of RNA-seq databases showed significantly decreasedFGFR2andITGB1mRNA levels in breast tumour samples, when compared to non-transformed tissues. Additionally, high risk healthy individuals were found to have disrupted correlation profiles of genes associated with FGFR2 and integrin signalling, cell adhesion/migration and ECM remodelling. Taken together, our results strongly suggest that FGFR2 loss with concomitant integrin β1 degradation is responsible for deregulation of epithelial cell-ECM interactions and this process may play an important role in the initiation of mammary gland epithelial tumorigenesis.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10911-023-09537-x.