Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential

Sreeharsha Gurrapu, Emanuela Pupo, Giulia Franzolin, Letizia Lanzetti, Luca Tamagnone*

*Corresponding author

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Semaphorin 4C (Sema4C) expression in human breast cancers correlates with poor disease outcome. Surprisingly, upon knock-down of Sema4C or its receptor PlexinB2 in diverse mammary carcinoma cells (but not their normal counterparts), we observed dramatic growth inhibition associated with impairment of G2/M phase transition, cytokinesis defects and the onset of cell senescence. Mechanistically, we demonstrated a Sema4C/PlexinB2/LARG-dependent signaling cascade that is required to maintain critical RhoA-GTP levels in cancer cells. Interestingly, we also found that Sema4C upregulation in luminal-type breast cancer cells drives a dramatic phenotypic change, with disassembly of polarity complexes, mitotic spindle misorientation, cell–cell dissociation and increased migration and invasiveness. We found that this signaling cascade is dependent on the PlexinB2 effectors ErbB2 and RhoA-dependent kinases. Moreover, Sema4C-overexpressing luminal breast cancer cells upregulated the transcription factors Snail, Slug and SOX-2, and formed estrogen-independent metastatic tumors in mice. In sum, our data indicate that Sema4C/PlexinB2 signaling is essential for the growth of breast carcinoma cells, featuring a novel potential therapeutic target. In addition, elevated Sema4C expression enables indolent luminal-type tumors to become resistant to estrogen deprivation, invasive and metastatic in vivo, which could account for its association with a subset of human breast cancers with poor prognosis.
Original languageEnglish
Pages (from-to)1259-1275
Number of pages17
JournalCell Death and Differentiation
Volume25
DOIs
Publication statusPublished - 2018

Keywords

  • Cancer biology
  • Cell Biology
  • Differentiation
  • Molecular Biology
  • Proliferation

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