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PTEN loss in the fallopian tube induces hyperplasia and ovarian tumor formation

Oncogene volume 37, pages 1976–1990 (2018)Cite this article

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Abstract

The signaling events involved in the onset of ovarian cancer from the fallopian tube epithelium (FTE) are crucial for early detection and treatment of the disease, but they remain poorly defined. Conditional homozygous knockout of PTEN mediated by PAX8-cre recombinase was sufficient to drive endometrioid and serous borderline ovarian carcinoma, providing the first model of FTE-derived borderline tumors. In addition, heterozygous PTEN deletion in the FTE resulted in hyperplasia, providing a model to study early events of human ovarian pathogenesis. To uncover the mechanism underlying the invasion of cancerous oviductal cells to the ovary, PTEN-deficient murine oviductal cells were developed and tagged with green fluorescent protein. Loss of PTEN increased cell migration, invasion, and upregulated WNT4, a key regulator of Müllerian duct development during embryogenesis. Further investigation revealed that WNT4 was required for increased migration and colonization of the ovary by PTEN-deficient oviductal cells in a β-catenin independent manner. Human tumor microarrays and ovarian cancer cells lines confirmed WNT4 expression in cancer and its role in migration. Together, these findings provide a novel model to study the mechanism of fallopian tube tumor initiation and invasion to the ovary mediated by loss of PTEN, which may help to define early events of human ovarian carcinogenesis.

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Acknowledgements

This work was supported by Tell Every Amazing Lady (T.E.A.L.) About Ovarian Cancer Louisa M. McGregor Ovarian Cancer Foundation, The American Cancer Society ACS RSG-12-230-01-TBG, the NIH UG3 ES029073-01 and the NIH T32 AT007533. We would also like to thank the Northwestern NUseq Core Facility and Dr. Matthew Schipma.

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Authors and Affiliations

  1. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA

    Angela Russo, Austin A. Czarnecki, Matthew Dean, Dimple A. Modi, Daniel D. Lantvit, Laura Hardy, Seth Baligod, David A. Davis & Joanna E. Burdette

  2. Department of Pathology, Reference Histology Laboratory,, J. Hopkins Medical Institution, Baltimore, MD, USA

    David A. Davis

  3. Department of Pathology, Northwestern University, Chicago, IL, USA

    Jian-Jun Wei

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Correspondence to Joanna E. Burdette.

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Russo, A., Czarnecki, A.A., Dean, M. et al. PTEN loss in the fallopian tube induces hyperplasia and ovarian tumor formation. Oncogene 37, 1976–1990 (2018). https://doi.org/10.1038/s41388-017-0097-8

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