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)