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.

Retracted: Silencing of COL1A2, COL6A3, and THBS2 inhibits gastric cancer cell proliferation, migration, and invasion while promoting apoptosis through the PI3k‐Akt signaling pathway

“…A decreased expression of COL6A3 (Collagen IV) was involved in the inflammation‐resistance process and helped to increase the content of triglyceride while promoting lipolysis and the phosphorylation of Akt . By inhibiting MCP1 expression, the PI3K/Akt signaling pathway was downregulated, thus leading to the promotion of the tumor cell apoptosis process . Additionally, Kim et al observed that THBS2 influences the proteolysis of tumor cytoplasm, thus contributing to the activation and expression of certain proteins in the PI3K/Akt signaling pathway.…”

Macrophages Regulate Unilateral Ureteral Obstruction-Induced Renal Lymphangiogenesis through C-C Motif Chemokine Receptor 2–Dependent Phosphatidylinositol 3-Kinase-AKT–Mechanistic Target of Rapamycin Signaling and Hypoxia-Inducible Factor-1α/Vascular Endothelial Growth Factor-C Expression

“…There is feasible evidence that ligation of MCP-1/CCL2 to CCR2 could be linked to PI3K/AKT/mTOR signaling. 30,31 We, therefore, first checked their activity by Western blot analysis. Indeed, loss of Ccr2 resulted in a significant reduction for the phosphorylated PI3K/AKT/mTOR, and even total levels for PI3Kp85 and mTOR were lower compared with that of WT mice after UUO induction.…”

“…To further dissect the molecular mechanisms by which loss of Ccr2 repressed VEGF-C expression in macrophages to attenuate UUO-induced lymphangiogenesis, we checked with the focus on the PI3K-AKT-mTOR pathway. 30,31 We first established that the infiltrated macrophages by UUO induction expressed high levels of CCR2 (Supplemental Figure S4). Western blot analysis was then performed to examine the PI3K-AKT-mTOR signaling.…”

Placenta Growth Factor Induces Invasion and Activates p70 during Rapamycin Treatment in Trophoblast Cells

“…6 mTOR is a kinase that is activated by phosphorylation in response to growth factors and other nutrients and regulates cell growth. [7][8][9] Eukaryotic translation initiation factor 4E binding protein I (4EBP1) and 70-kDa ribosomal protein kinase I (p70) are downstream effectors of mTOR, which activate translation and protein synthesis and cause cell proliferation. 10,11 Studies show that mTOR acts as a nutrient sensor and correlates with the proliferation of trophoblast cells and may contribute to first trimester trophoblast invasion.…”