title: Non-tumorigenic epithelial cells secrete MCP-1 and other cytokines that promote cell division in breast cancer cells by activating ERα via PI3K/Akt/mTOR signaling.
abstract: Efforts in understanding the role of the microenvironment in the development of breast cancer have focused on tumor-stroma cross-talk, but the possibility that normal epithelial cells might also play a role in tumor progression has received little attention. Here, we show that non-tumorigenic human mammary epithelial cells (MCF10A and HMEC) secrete factors able to enhance the proliferation of estrogen receptor α (ERα) positive breast cancer cells (MCF7 and T47D) and suppress their ability to undergo apoptosis. Conditioned medium (CM) derived from MCF10A and HMEC cells was capable of activating ERα in a hormone-independent way, by phosphorylating ERα on Ser167. Co-exposure with PI3K and mTORC1 inhibitors significantly reduced the ERα Ser167 phosphorylation and suppressed the proliferation-enhancing effects of both 10A-CM and HMEC-CM on MCF7 cells. We show that MCF10A and HMEC secrete numerous cytokines, among them MCP-1, which was one of the most prevalent. MCP-1 was shown to have a role in the effects elicited by the 10A-CM. It activated the ERα by phosphorylating Ser167 via the PI3K/Akt/mTORC1 signaling pathway, an effect which was further confirmed by silencing the MCP-1 receptors, CCR2 and CCR4. To our knowledge, this is the first time MCP-1 has been shown to contribute to ERα signaling activation. These data suggest that normal mammary cells could have the capability of supporting the proliferation of breast cancer cells via paracrine interactions. A better understanding of the role of these cells may be useful for designing strategies for the prevention of tumor progression at early stages.
authors.affiliation: UCL School of Pharmacy, 20-39 Brunswick Square, WC1N 1AX London, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Riverso
authors.affiliation: Brunel University, Institute for the Environment, Kingston Lane, UB8 3PH Uxbridge, Middlesex, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kortenkamp
authors.affiliation: Brunel University, Institute for the Environment, Kingston Lane, UB8 3PH Uxbridge, Middlesex, UK. Electronic address: elisabete.silva@brunel.ac.uk.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Silva
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D018932:Chemokine CCL2; D047628:Estrogen Receptor alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C111835:CCL2 protein, human; C506487:ESR1 protein, human; C546842:MTOR protein, human
keywords: Breast cancer; Estrogen receptor; MCP-1; Tumor microenvironment