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BACKGROUND: PolyADP ribosylation (PARylation) by PARP1 is a significant post-translational modification affecting protein function in various cancers. However, PARP1 mediated cellular processes in the context of breast cancer are not fully understood. METHOD: To identify potential targets of PARP1, we carried out whole transcriptome sequencing with shRNA mediated PARP1 knockdown in triple-negative breast cancer (TNBC) cell line and inhibited PARP1 with a known PARP1 inhibitor, PJ34. RESULTS: Analysis of the transcriptomics data revealed that PARP1 is involved in regulating multiple chemokines under basal conditions, including the chemokine ligand 2 (CCL2). PARP1 knockdown and PJ34 mediated inhibition showed reduced CCL2 transcript levels in breast cancer cells, corroborating the findings from the sequencing data. We further showed that PARP1 interacts with the NFκB P65 subunit to regulate transcription of CCL2. Using chromatin immunoprecipitation, we confirm that both PARP1 and P65 localize to the promoter of CCL2, suggesting direct regulation of CCL2 promoter activity. CCL2, in turn, can positively affect the PARP1 pathway, as global PARylation levels increased upon CCL2 treatment. CONCLUSION: Our results indicate crosstalk between PARP1 and CCL2, which is critical for maintaining CCL2 levels in breast cancer cells and subsequently drives cellular invasiveness.
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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.