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

Oncogene volume 39, pages 2772–2785 (2020)Cite this article

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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.

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Fig. 1: SEMA7A promotes growth and invasion in PPBC.
Fig. 2: SEMA7A expression is increased in DCIS patient samples.
Fig. 3: SEMA7A expression is sufficient to drive tumor growth and invasion.
Fig. 4: SEMA7A promotes invasion via fibroblast-mediated collagen deposition.
Fig. 5: SEMA7A promotes mesenchymal protein expression and phenotypes.
Fig. 6: SEMA7A promotes cell survival via fibronectin.
Fig. 7: SEMA7A drives metastatic seeding and poor prognosis in patients.
Fig. 8: Model depicting SEMA7A-mediated invasion and cell survival.

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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.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Medicine, CU Anschutz Medical Campus, Aurora, CO, 80045, USA

    Sarah E. Tarullo, Virginia F. Borges & Traci R. Lyons

  2. Young Women’s BC Translational Program, CU Anschutz Medical Campus, Aurora, CO, 80045, USA

    Sarah E. Tarullo, Virginia F. Borges & Traci R. Lyons

  3. Department of Biochemistry and Molecular Genetics, CU Anschutz Medical Campus, Aurora, CO, 80045, USA

    Ryan C. Hill & Kirk C. Hansen

  4. Division of Cancer and Developmental Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Fariba Behbod

  5. University of Colorado Cancer Center, Aurora, CO, 80045, USA

    Virginia F. Borges & Traci R. Lyons

  6. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA

    Andrew C. Nelson

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Contributions

SET and TRL conceived and designed the study. SET performed all in vitro and in vivo studies. VFB and FB were responsible for regulatory oversight of human tissue acquisition and providing cases for IHC analysis. RCH and KH were responsible for all mass spectrometry experiments and associated data analysis. ACN was responsible for analyzing and scoring all tumor for invasion. SET and TRL were responsible for hypothesis development, conceptual design, data analysis, and data interpretation. SET and TRL wrote the manuscript with all authors providing critical evaluation.

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Correspondence to Traci R. Lyons.

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Tarullo, S.E., Hill, R.C., Hansen, K.C. et al. Postpartum breast cancer progression is driven by semaphorin 7a-mediated invasion and survival. Oncogene 39, 2772–2785 (2020). https://doi.org/10.1038/s41388-020-1192-9

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