Our data demonstrate that hypoxia (2% O(2)) or desferrioxamine (DFO) induces tyrosine and serine phosphorylation of STAT5 in human breast cancer cells (MCF-7) and mammary epithelial cells (HC11).
RNA interference of CCR2 expression in breast cancer cells significantly inhibited CCL2-induced migration, survival, and phosphorylation of Smad3 and p42/44MAPK proteins.
Treatment of immunodeficient mice bearing human breast cancer cells with a neutralizing antibody to MCP-1 resulted in significant decrease of macrophage infiltration, angiogenetic activity and tumor growth.
Specifically, IL-6 promoted the proliferation of normal cells and CCL2 induced the M2-like polarization of macrophages, which might create an immunosuppressive microenvironment during the initiation and/or development of breast cancer.
In line with the tumor-promoting roles of CCL2 and CCL5 in breast cancer, the two chemokines were shown to mediate many types of tumor-promoting cross-talks between the tumor cells and cells of the tumor microenvironment: (1) they shift the balance at the tumor site between different leukocyte cell types by increasing the presence of deleterious tumor-associated macrophages (TAM) and inhibiting potential anti-tumor T cell activities; (2) of the two chemokines, mainly CCL2 promotes angiogenesis; (3) CCL2 and CCL5 which are expressed by cells of the tumor microenvironment osteoblasts and mesenchymal stem cells play a role in breast metastatic processes.
Indeed, inhibiting Myd88 function in four different murine mammary carcinomas as well as the human breast cancer cell line MDA-MB-231 led to decreased growth as well as CCL2 and CCL5 expression.
We conclude that CCL2 secreted by TAMs activates PI3K/Akt/mTOR signaling and promotes an endocrine resistance feedback loop in the TME, suggesting that CCL2 and TAMs may be novel therapeutic targets for patients with endocrine-resistant breast cancer.
This study also indicates that targeting breast cancer cell p38β and its product MCP-1 may be a viable approach to treat or prevent bone destruction in patients with bone-metastatic breast cancer.
In this work, mammary epithelial (EpH4 and HC11) and breast cancer (MC4-L2) cells with endogenous ERα and ERβ expression and T47-D human breast cancer cells with recombinant ERβ (T47-DERβ) were used to explore effects exerted in vitro and in vivo by the ERβ agonists 2,3-bis (4-hydroxy-phenyl)-propionitrile (DPN) and 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (WAY).
Finally, knockdown of PIAS3 with siRNA partially rescued the inhibitory effect of the ErbB4 ICD on differentiation of MDA-MB-468 breast cancer and HC11 mammary epithelial cells.
Media conditioned by the MDA-MB-231 cells promoted the expansion, chemotactic migration, and immunosuppressive activity of Tregs, and these effects were attenuated in a dose-dependent manner by ZA treatment, and the attenuation was due to reduced expression of selected breast cancer cell factors (CCL2, CCL5, and IDO).
Our findings shed new light on the mechanisms underlying the progression of ER(+) breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways.
To that effect, polymorphisms in genes coding for IL-4 (IL-4 C-590T; rs2243250), IFN-γ (IFN-G A + 874T; rs2430561) and MCP-1 (MCP-1A-2578G; rs1024611) were examined in premenopausal, healthy women (N = 239) and patients with breast cancer (N = 182) from western India.
Our results did not show association of the CCL2 -2518 A>G polymorphism with breast cancer occurrence and clinical characteristics in a sample of the Polish cohort.
Here, we identified the impact of TNF-α and IL-1β on the inflammatory phenotype of CAFs and MSCs by determining the expression of inflammatory chemokines that are well-characterized as pro-tumorigenic in breast cancer: CCL2 (MCP-1), CXCL8 (IL-8) and CCL5 (RANTES).