Molecular Carcinogenesis 2015-05-01

Crosstalk between VEGF and MTA1 signaling pathways contribute to aggressiveness of breast carcinoma.

Sachin Raj M Nagaraj, Puttananjaiah Shilpa, Kavitha Rachaiah, Bharathi P Salimath

Index: Mol. Carcinog. 54(5) , 333-50, (2015)

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Abstract

The expression of metastasis associated protein (MTA1) correlates well with tumor metastasis; however its role as a proangiogenic protein and the molecular mechanisms underlying the same are not fully understood. In this study the MTA1 protein was expressed and purified to evaluate its angiogenic potential. In both MCF-7 and MDA-MB-231 cells, endogenous MTA1 protein was localized in the nucleus; while added recombinant MTA1 protein was bound to cell membrane as per immunofluorescence data. MTA1 was detected both in conditioned media and in human serum samples. Recombinant MTA1 regulated cellular functions of HUVEC's such as, proliferation, tube formation, and migration. MTA1 was more potent than VEGF in inducing invasion of breast cancer cells. Analogous to VEGF, MTA1 could induce angiogenesis in both non-tumor and tumor context, as verified by rat cornea, shell less CAM and xenograft models respectively. However MTA-1 was more potent an inducer of angiogenesis. VEGF or Flt-1 gene promoter, luciferase gene reporter analysis revealed that MTA1 up regulates the expression of VEGF and its receptor Flt-1 genes. Kinetics of VEGF-induced expression of MTA1 and qPCR studies showed that there is an increased expression of MTA1 in tumor cells. VEGF induced phosphorylation of endogenous MTA1 on tyrosine residues; phosphorylation was mediated through VEGFR2 and p38-MAP kinase. Recombinant MTA1 activated signaling, in MCF-7 and MDA-MB-231 cells, involved ERK and JNK pathways. In conclusion, MTA1 is a potent angiogenic molecule and cross talk between VEGF and MTA1 protein regulates tumor angiogenesis and metastasis.© 2013 Wiley Periodicals, Inc.