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The microenvironment has been shown to play an important role in the various steps of tumour development. The main research efforts to date have focused on the tumour-stroma cross-talk, but the possibility that normal epithelial cells might also play a role in tumour progression has received little attention. The aim of this project was to study cell-cell interactions and evaluate how normal cells can influence the proliferation and apoptosis of cancer cells. Furthermore, this study aimed to delineate the signalling pathways underlying these paracrine communications and identify new potential molecular targets for therapy. To address these questions, the breast cancer cell line MCF7 and the normal mammary epithelial cells MCF10A and HMEC were used. Here, we show that non-tumorigenic mammary epithelial cells secrete factors able to enhance the proliferation of ERα+ breast cancer cells and suppress their ability to undergo apoptosis. Conditioned medium derived from MCF10A and HMEC cells (10A-CM and HMEC-CM) was capable of activating ERα in a hormone-independent manner via the PI3K/Akt/mTORC1 pathway. Finally, a cytokine antibody analysis of the conditioned media allowed the identification of MCP-1 as one of the most prevalent cytokines in the 10A-CM. We found that this cytokine recapitulates the effects of 10A-CM and HMEC-CM, as it promoted MCF7 cell proliferation. Interestingly, MCP-1 activated the ERα by phosphorylating Ser167 via PI3K/Akt/mTORC1, as demonstrated also by silencing its receptors, CCR2 and CCR4. To our knowledge, this is the first demonstration that MCP-1 is involved in the activation of ERα signalling. Together, our data indicate that normal mammary cells support the proliferation of breast cancer cells via paracrine interactions. As this communication occurs within the terminal ductal lobular units, before the cross-talk between tumour and stroma takes place, a better understanding of the role of these cells may be useful for designing drugs that will prevent the progression of the tumour at its early stages. |
