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First trimester human placental factors induce breast cancer cell autophagy

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Abstract

Placental factors, progesterone included, facilitate breast cancer cell line (BCCL) motility and thus may contribute to the advanced breast cancer found during pregnancy. Cancer and placental implantations are similar; the last is accompanied by extravillous trophoblast cell invasion and autophagy which are interlinked. We aimed to analyze the effect of first trimester human placenta on BCCL autophagy. BCCLs (MCF-7/T47D) were cultured with placental explants (60 h) or placental supernatants (24 h). Following cultures, BCCLs were sorted out for RNA/protein extraction. RNA served for microarray/qPCR (BNIP3) and protein for Western blot (HIF1α, LC3BII) analyses. Inhibitors were added to the placenta-MCF-7 coculture or placental supernatants (autophagy inhibitor-3MA, progesterone receptor (PR) inhibitor-RU486, and HIF1α inhibitor-Vitexin) in order to evaluate their effects on BCCL motility and LC3BII/HIF1α expression. LC3BII (an autophagy marker) expression was elevated in BCCLs following placental explant coculture and exposure to placental supernatants. The autophagy inhibitor (3MA) repressed the placenta-induced MCF-7/T47D migration, establishing a connection between BCCL autophagy and migration. Microarray analysis of MCF-7 following placenta-MCF-7 coculture showed that “HIF1α pathway,” a known autophagy facilitator, was significantly manipulated. Indeed, placental factors elevated HIF1α and its target BNIP3 in the BCCLs, verifying array results. Lastly, PR inhibitor reduced HIF1α expression and both PR and HIF1α inhibitors reduced MCF-7 LC3BII expression and motility, suggesting involvement of the PR-HIF1α axis in the autophagy process. Placental factors induced BCCL autophagy that is interlinked to their motility. This suggests that autophagy-related molecules may serve as targets for therapy in pregnancy-associated breast cancer.

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Acknowledgments

This work constitutes a section of the PhD thesis of Epstein Shochet Gali, Sackler Faculty of Medicine, Tel Aviv University, Israel.

Conflict of interest

The authors declare no conflict of interest.

Funding

This work was supported by the ‘Dr Leo Mintz Foundation’ of the Sackler Faculty of Medicine, Tel Aviv University, Israel.

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    Authors and Affiliations

    1. Oncogenetic Laboratory, Meir Medical Center, 45 Tschernichovski St., 44281, Kfar Saba, Israel

      G. Epstein Shochet, L. Drucker, S. Tartakover Matalon & M. Lishner

    2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

      G. Epstein Shochet, L. Drucker, M. Pomeranz, A. Fishman, S. Tartakover Matalon & M. Lishner

    3. Department of Obstetrics & Gynecology, Meir Medical Center, Kfar Saba, Israel

      M. Pomeranz & A. Fishman

    4. Bioinformatics Unit, Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

      M. Pasmanik-Chor

    5. Department of internal Medicine A, Meir Medical Center, Kfar Saba, Israel

      M. Lishner

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    Correspondence to S. Tartakover Matalon.

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    S. Tartakover Matalon and M. Lishner have contributed equally to this work.

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    Epstein Shochet, G., Drucker, L., Pasmanik-Chor, M. et al. First trimester human placental factors induce breast cancer cell autophagy. Breast Cancer Res Treat 149, 645–654 (2015). https://doi.org/10.1007/s10549-015-3266-x

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