title: Semaphorin 3A upregulates FOXO 3a-dependent MelCAM expression leading to attenuation of breast tumor growth and angiogenesis.
abstract: Semaphorin 3A (Sema 3A), a member of semaphorin family, serves as a guidance clue during embryonic development and is known as a candidate tumor suppressor that attenuates breast tumor progression by binding with its co-receptor, neuropilin-1 (NRP-1). However, the underlying mechanism by which Sema 3A suppresses breast tumor growth is still unexplored. In this study, we report that Sema 3A regulates phosphorylation and nuclear translocation of phosphatase and tensin homolog (PTEN) and FOXO 3a. Moreover, Sema 3A controls NRP-1-mediated PTEN-dependent FOXO 3a activation. Overexpression of PTEN and FOXO 3a enhances Sema 3A-induced attenuation of breast cancer cell migration. Chromatin immunoprecipitation and electrophoretic mobility shift assay data revealed that FOXO 3a regulates MelCAM at the transcriptional level. Furthermore, Sema 3A induces NRP-1-mediated MelCAM expression through PTEN and FOXO 3a. The data also showed that vascular endothelial growth factor-induced angiogenesis is inhibited by Sema 3A. Loss of or gain in function study revealed that Sema 3A modulates phosphorylation of PTEN and FOXO 3a and expression of MelCAM, leading to suppression of tumor growth and angiogenesis using in vivo mice model. Clinical specimen analysis revealed that reduced expression of Sema 3A and p-PTEN are correlated with enhanced breast cancer progression, further strengthening our in vitro and in vivo findings. Correlation of relapse-free survival of breast cancer patients (n=2878) with expression levels of Sema 3A, NRP-1, FOXO 3a and MelCAM were studied by Kaplan-Meier analysis. Statistical analysis revealed a close association between reduced expression of Sema 3A and MelCAM with that of poor patient's survival. Our study demonstrated a novel mechanism of regulation of tumor suppression by Sema 3A in coordination with a chain of tumor-suppressor genes, which in turn inhibits breast cancer cell migration, tumor growth and angiogenesis.
authors.affiliation: Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Center for Cell Science (NCCS), Pune, India.
authors.forename: R
authors.initials: R
authors.lastname: Mishra
authors.affiliation: Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Center for Cell Science (NCCS), Pune, India.
authors.forename: D
authors.initials: D
authors.lastname: Thorat
authors.affiliation: Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Center for Cell Science (NCCS), Pune, India.
authors.forename: G
authors.initials: G
authors.lastname: Soundararajan
authors.affiliation: Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Center for Cell Science (NCCS), Pune, India.
authors.forename: S J
authors.initials: SJ
authors.lastname: Pradhan
authors.affiliation: Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Chakraborty
authors.affiliation: Grant Medical Foundation, Ruby Hall Clinic, Pune, India.
authors.forename: K
authors.initials: K
authors.lastname: Lohite
authors.affiliation: Grant Medical Foundation, Ruby Hall Clinic, Pune, India.
authors.forename: S
authors.initials: S
authors.lastname: Karnik
authors.affiliation: Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Center for Cell Science (NCCS), Pune, India.
authors.forename: G C
authors.initials: GC
authors.lastname: Kundu
mesh_terms: D000818:Animals; D001940:Breast / Q000098:blood supply / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D051929:CD146 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D040121:Semaphorin-3A / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051929:CD146 Antigen; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C497902:MCAM protein, human; C108639:SEMA3A protein, human; D040121:Semaphorin-3A; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
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