Postpartum breast cancer progression is driven by semaphorin 7a-mediated invasion and survival

Sarah E. Tarullo, Ryan C. Hill, Kirk C. Hansen, Fariba Behbod, Virginia F. Borges, Andrew C. Nelson, Traci R. Lyons

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Young women diagnosed with breast cancer (BC) have poor prognosis due to increased rates of metastasis. In addition, women diagnosed within 10 years of most recent childbirth are approximately three times more likely to develop metastasis than age- and stage-matched nulliparous women. We define these cases as postpartum BC (PPBC) and propose that the unique biology of the postpartum mammary gland drives tumor progression. Our published results revealed roles for SEMA7A in breast tumor cell growth, motility, invasion, and tumor-associated lymphangiogenesis, all of which are also increased in preclinical models of PPBC. However, whether SEMA7A drives progression in PPBC remains largely unexplored. Our results presented herein show that silencing of SEMA7A decreases tumor growth in a model of PPBC, while overexpression is sufficient to increase growth in nulliparous hosts. Further, we show that SEMA7A promotes multiple known drivers of PPBC progression including tumor-associated COX-2 expression and fibroblast-mediated collagen deposition in the tumor microenvironment. In addition, we show for the first time that SEMA7A-expressing cells deposit fibronectin to promote tumor cell survival. Finally, we show that co-expression of SEMA7A/COX-2/FN predicts for poor prognosis in breast cancer patient cohorts. These studies suggest SEMA7A as a key mediator of BC progression, and that targeting SEMA7A may open avenues for novel therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)2772-2785
Number of pages14
JournalOncogene
Volume39
Issue number13
DOIs
StatePublished - Mar 2020

Bibliographical note

Funding Information:
Acknowledgements MCF10DCIS cells were obtained from K. Polyak and A. Marusyk (Harvard University, Cambridge, MA). MDA-MB-231 cells were obtained from P. Schedin (Oregon Heath and Sciences University, Portland OR). HLF-1 cells were gifted from M. Fini (CU Anschutz Medical Campus, Denver, CO). We thank H. Ford for the pcDNA3.1 vector (CU Anschutz Medical Campus, Denver, CO) and R. Medzhitov (Yale University, New Haven, CT) for the SEMA7A-Fc overexpression vector. We also acknowledge V. Wessells, A. Elder, L. Crump, T. Wallace, C. Young, A. Stoller, M. Kobritz, and C. Hoang for technical support and advice. This work was supported by the American Cancer Society (RSG 16-171-01-CSM) and NIH/NCI (R01CA211696-01A1) to TRL and NIH/CCTSI/CTSA (TL1 TR001081) to SET.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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