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.
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Acknowledgements
We gratefully acknowledge the help of S. Giordano, E. Medico, S. Corso, C Isella, M. Rehman, S. Rizzolio, G. Cagnoni and C. Battistini for useful discussion and suggestions. We thank S. Bolla, L. Palmas and F. Sassi for skillful technical assistance; M. Accardo and L. Tarditi for support with experiments in mice; B. Lupo for help with QPCR analysis. The work was supported by grants from the Italian Association for Cancer Research (AIRC-IG # 2014-15179 to LT; and AIRC-IG #15180 to LL), and the Fondazione Piemontese per la Ricerca sul Cancro (grants FPRC-5perMille-MIUR-2013 to LT, FPRC-5perMille-Ministero Salute-2013 to LT and FPRC 5xmille Ministero Salute 2015 to LL).
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Gurrapu, S., Pupo, E., Franzolin, G. et al. Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential. Cell Death Differ 25, 1259–1275 (2018). https://doi.org/10.1038/s41418-018-0097-4
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DOI: https://doi.org/10.1038/s41418-018-0097-4
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