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Breast cancer cells and activated tumor stroma fibroblasts communicate through secretion of soluble factors. Estradiol (E2), EGF and IGF-I are among the most important molecules contributing to breast cancer progression. We have shown that E2, via estrogen receptors (ERs), regulates the expression of extracellular matrix (ECM) macromolecules. ECM effectors, such as proteoglycans, integrins, metalloproteinases and their endogenous inhibitors are key players in the organization of tumor microenvironment.
Ongoing studies indicate that the intracellular communication (cross-talk) between the activated ?•2 - ERα/β complexes and the EGFR and IGFR significantly influences the expression of certain ECM macromolecules. This, in turn, may affect the functional properties of cancer cells (proliferation, adherence, migration and metastatic potential) as well as the induction of EMT (epithelial to mesenchymal transition). The role of the two ER forms, ERα/β, in such a cross-talk and the induction EMT has not yet clarified.
The aim of this project is, therefore, to clarify:
- the role of the two ER forms (ERα/β) in the cross-talk with IGFR and EGFR, and
- the role of proteasome and the paracrine interactions of cancer cells with stromal fibroblasts, in the induction EMT, the expression of macromolecules by cancer cells and their functional properties.
Experimental studies will be performed in breast cancer cells of different ER profile and invasive potential in presence of stimuli and primary breast stromal fibroblasts-derived soluble factors.
This project involves 6 workpackages. The workload is distributed among the participating institutes according to expertise of the investigators.
The results of this collaborative project will help to a deeper understanding of the critical role of E2-ERα/β cross-talk with IGF-IR and EGFR in the progression of breast cancer. This will be the basis to identify novel molecular targets for efficient prognosis and pharmacological targeting.
