CCR2 Chemokine Receptors Enhance Growth and Cell-Cycle Progression of Breast Cancer Cells through SRC and PKC Activation

Abstract

Basal-like breast cancers are an aggressive breast cancer subtype, which often lack estrogen receptor, progesterone receptor, and Her2 expression, and are resistant to antihormonal and targeted therapy, resulting in few treatment options. Understanding the underlying mechanisms that regulate progression of basal-like breast cancers would lead to new therapeutic targets and improved treatment strategies. Breast cancer progression is characterized by inflammatory responses, regulated in part by chemokines. The CCL2/CCR2 chemokine pathway is best known for regulating breast cancer progression through macrophage-dependent mechanisms. Here, we demonstrated important biological roles for CCL2/CCR2 signaling in breast cancer cells. Using the MCF10CA1d xenograft model of basal-like breast cancer, primary tumor growth was significantly increased with cotransplantation of patient-derived fibroblasts expressing high levels of CCL2, and was inhibited with CRISP/R gene ablation of stromal CCL2. CRISP/R gene ablation of CCR2 in MCF10CA1d breast cancer cells inhibited breast tumor growth and M2 macrophage recruitment and validated through CCR2 shRNA knockdown in the 4T1 model. Reverse phase protein array analysis revealed that cell-cycle protein expression was associated with CCR2 expression in basal-like breast cancer cells. CCL2 treatment of basal-like breast cancer cell lines increased proliferation and cell-cycle progression associated with SRC and PKC activation. Through pharmacologic approaches, we demonstrated that SRC and PKC negatively regulated expression of the cell-cycle inhibitor protein p27KIP1, and are necessary for CCL2-induced breast cancer cell proliferation.Implications: This report sheds novel light on CCL2/ CCR2 chemokine signaling as a mitogenic pathway and cell-cycle regulator in breast cancer cells.

IL-4 receptor targeting as an effective immunotherapy against triple-negative breast cancer

“…To further characterize the in vivo effect of DABIL-4 upon the metastatic potential, we analyzed total RNA isolated from the primary tumors using the NanoString PanCancer Immune Profiling Panel Assay. We noted significant declines in the level of several transcripts associated with metastasis (Cd36 (15), Egr3 (16)(17)(18) and Maf (19)) and tumorigenesis (Ccr2 (20), Ccr6 (21)) in many solid tumors including breast cancer (Fig 4 and Table 1). We also observed an increased levels of the C200r1 transcript which is associated with inhibition of metastasis and tumorigenesis (22,23) (Fig 4 and Table 1).…”

Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers

“…Even though CCL2 exhibits angiogenic effects in vivo, the activity is only observed at certain doses but not at higher doses of CCL2 [154]. Nevertheless, there is a series of results suggesting that the CCL2-dependent signalling pathway could promote the survival of tumor cells [155,156] and stimulate metastasis [157][158][159] and angiogenesis [121]. The dual roles of the CCL2/CCR2 axis in cancer development can lead to opposite results, as patients with higher CCL2 or CCR2 expression had significantly better OS in NSCLC [153] but shorter OS and progression-free survival in diffuse large B cell lymphoma (DLBCL) [160], although evidence about the roles of CCL2/CCR2 in DLBCL is limited.…”

Identification of Candidate Genes in Early-Stage Invasive Ductal Carcinoma Patients with High-Risk Mortality using 32 Genes Commonly Involved in Breast Cancer: A Retrospective Study

“…SRC [V-Src Avian Sarcoma (Schmidt-Ruppin A-2) Viral Oncogene Homolog] encodes the non-receptor protein tyrosine kinase, which plays a role in the regulation of cell proliferation, migration, and survival [28]. The SRC mutation is known to be involved in malignant progression [29,30]. Increased SRC activation is correlated with trastuzumab resistance and interacts with estrogen receptors.…”