MCP-1 is overexpressed in triple-negative breast cancers and drives cancer invasiveness and metastasis

Breast Cancer Research and Treatment, Mar 2018

Background Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer that lacks ER/PR and HER2 receptors. Hence, there is urgency in developing new or novel therapeutic strategies for treatment of TNBC. Our study shows that the Monocyte Chemoattractant Protein-1 (MCP-1) is a marker associated with TNBC and may play a key role in TNBC disease progression. Experimental design ELISA method was used to measure secreted MCP-1, and mRNA levels were determined by Real-time PCR in numerous cancer cell lines, representing various breast cancer subtypes. Cellular invasiveness was determined by Boyden chamber assay. Results Our data show that MCP-1 is upregulated in TNBC cell lines both transcriptionally as well as in secreted protein levels compared to ER-positive luminal cell line, MCF-7. Breast cancer patients, with Basal or Claudin-low subtypes, also showed high expression of MCP-1. MCP-1 treatment induced cell invasion in various breast cancer cell types, without affecting cell proliferation. Small molecule antagonists against Chemokine Receptor 2 (CCR2), cognate receptor for MCP-1 as well as the MAP kinase pathway inhibitor U0126 negatively affected MCP-1 induced MCF-7 cell invasion. This suggests that MCP-1-CCR2 axis may regulate invasiveness via the MAP Kinase pathway. Knocking down MCP-1 decreased cell invasion in TNBC cell line BT-549, along with downregulation of key epithelial to mesenchymal transition markers, N-cadherin and Vimentin. Conclusion Our study suggests that MCP-1 mediated pathways could be potential therapeutic targets for the treatment of TNBC, and could reduce cancer health disparities.

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MCP-1 is overexpressed in triple-negative breast cancers and drives cancer invasiveness and metastasis

MCP‑1 is overexpressed in triple‑negative breast cancers and drives cancer invasiveness and metastasis Pranabananda Dutta 0 1 Marianna Sarkissyan 0 1 Kimberly Paico 0 1 Yanyuan Wu 0 1 Jaydutt V. Vadgama 0 1 0 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles , Los Angeles, CA , USA 1 Division of Cancer Research and Training, Department of Medicine, Charles R. Drew University of Medicine and Science , 1731 East 120th Street, Los Angeles, CA 90059 , USA 2 Jaydutt V. Vadgama Background Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer that lacks ER/PR and HER2 receptors. Hence, there is urgency in developing new or novel therapeutic strategies for treatment of TNBC. Our study shows that the Monocyte Chemoattractant Protein-1 (MCP-1) is a marker associated with TNBC and may play a key role in TNBC disease progression. Experimental design ELISA method was used to measure secreted MCP-1, and mRNA levels were determined by Real-time PCR in numerous cancer cell lines, representing various breast cancer subtypes. Cellular invasiveness was determined by Boyden chamber assay. Results Our data show that MCP-1 is upregulated in TNBC cell lines both transcriptionally as well as in secreted protein levels compared to ER-positive luminal cell line, MCF-7. Breast cancer patients, with Basal or Claudin-low subtypes, also showed high expression of MCP-1. MCP-1 treatment induced cell invasion in various breast cancer cell types, without affecting cell proliferation. Small molecule antagonists against Chemokine Receptor 2 (CCR2), cognate receptor for MCP-1 as well as the MAP kinase pathway inhibitor U0126 negatively affected MCP-1 induced MCF-7 cell invasion. This suggests that MCP-1-CCR2 axis may regulate invasiveness via the MAP Kinase pathway. Knocking down MCP-1 decreased cell invasion in TNBC cell line BT-549, along with downregulation of key epithelial to mesenchymal transition markers, N-cadherin and Vimentin. Conclusion Our study suggests that MCP-1 mediated pathways could be potential therapeutic targets for the treatment of TNBC, and could reduce cancer health disparities. MCP-1; TNBC; Metastasis; MAP kinase Introduction Breast cancer is the second leading cause of mortality in women. According to SEER (surveillance, epidemiology, and end result program: seer.cancer.gov), more than 200 thousand new breast cancer cases were diagnosed in 2016 in the United States. The estimated death remains to be more than 40 thousand cases in the same year. Between the various histological subtypes of breast cancer, Triplenegative breast cancer (TNBC) comprises only 15–20% of total breast cancer cases. However, thus far, TNBC is difficult to treat due to the lack of any targeted therapy [ 1, 2 ]. TNBCs do not express estrogen (ER) or progesterone (PR) receptors or HER2 and lack specific biomarkers that could be correlated with disease incidence and progression [3]. TNBCs represent a significant health disparity as these occur at higher rates in African-American (AA) women compared to European-American women. TNBCs are also diagnosed at younger ages (< 40 years) [ 4 ]. Thus far, the biological factors responsible for this health disparity in TNBC are unknown. Therefore, understanding the cellular or molecular nature of this health disparity is critical so that we can develop better treatment options for this type of breast cancer. Obesity is a well-known comorbidity in breast cancer and could contribute to this disparity as well. Obese African-American breast cancer patients have been shown to have lower disease-free survival compared with nonobese counterparts [ 5 ]. Obesity-related inflammation has been shown to involve crosstalk between cancer cells and its microenvironment via chemokines that cause metastasis [ 6 ]. Monocyte Chemoattractant protein 1 (MCP-1) is one such inflammatory chemokine implicated in cancer development and progression [ 7 ]. MCP-1 is a member of the C–C motif chemokine family. It is encoded from a locus at human Chromosome 17 and comprises of 76 amino acids [ 8 ]. It is a 12kd protein that is secreted from the cell and binds to its receptor CCR2. The receptor for MCP-1 is a G-protein coupled receptor that activates downstream components upon ligand binding. We have previously observed that MCP-1, along with GROα, serum levels were high in obese AA breast cancer patients compared with nonobese patients (unpublished observation). Cytokines like GROα was found to be highly expressed in TNBC and was associated with metastasis [ 9 ]. In our current study, we show that higher MCP-1 levels are also associated with cell invasion and metastasis in breast cancer. Here we demonstrate that, MCP-1 is highly expressed in breast cancer cells. Importantly, the expression levels in TNBC tumor cells are higher compared with other subtypes of breast cancer cells. Although, MCP-1 modestly affects cellular proliferation (...truncated)


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Pranabananda Dutta, Marianna Sarkissyan, Kimberly Paico, Yanyuan Wu, Jaydutt V. Vadgama. MCP-1 is overexpressed in triple-negative breast cancers and drives cancer invasiveness and metastasis, Breast Cancer Research and Treatment, 2018, pp. 1-10, DOI: 10.1007/s10549-018-4760-8