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Loss of LKB1 and p53 synergizes to alter fallopian tube epithelial phenotype and high-grade serous tumorigenesis

Oncogene volume 35, pages 59–68 (2016)Cite this article

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Abstract

Liver kinase B1 (LKB1) is a tumor suppressor ubiquitously expressed serine/threonine protein kinase involved in energy metabolism and cellular polarity. In microarray experiments that compared normal tubal epithelium with high-grade serous carcinoma (HGSC), we observed a decrease in LKB1 mRNA expression in HGSC. In this study, we demonstrate that loss of cytoplasmic and nuclear LKB1 protein expression is frequently observed in tubal cancer precursor lesions as well as in both sporadic and hereditary HGSCs compared with other ovarian cancer histotypes. Bi-allelic genomic loss of LKB1 in HGSC did not account for the majority of cases with a decrease in protein expression. In vitro, shLKB1-fallopian tube epithelial (FTE) cells underwent premature cellular arrest and in ex vivo FTE culture, LKB1 loss and p53 mutant synergized to disrupt apical to basal polarity and decrease the number of ciliated cells. Overexpression of cyclin E1 allowed for bypass of LKB1-induced cellular arrest, and increased both proliferation and anchorage-independent growth of transformed FTE cells. These data suggest that LKB1 loss early in ovarian serous tumorigenesis has an integral role in tumor promotion by disrupting apical to basal polarity in the presence of mutated p53 in fallopian tube cells.

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Acknowledgements

We thank the UHN Cancer Biobank Core Laboratory for sample acquisition, the UHN Pathology Research Program for immunohistochemistry, Doug Holmyard at Mount Sinai Hospital for the SEM, as well as the Gynecological Oncologists at the Princess Margaret Cancer Centre. This study was funded by the CDMRP Ovarian Cancer program (W81WH-0701-0371) and the Princess Margaret Cancer Centre Foundation.

Author Contributions

SG and PS contributed to conception and design; SG, AM and PS contributed to development of methodology; SG, AM, RS, RC and AT contributed to acquisition of data; SG, AM, RS, RC and PS contributed to analysis and interpretation of data; SG and PS contributed to writing.

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Authors and Affiliations

  1. Campbell Family Institute for Breast Cancer Research, Toronto,, Ontario, Canada

    S H L George, A Milea, R Sowamber, R Chehade, A Tone & P A Shaw

  2. Ontario Cancer Institute,, Toronto,, Ontario, Canada

    S H L George, A Milea, R Sowamber, R Chehade & P A Shaw

  3. Department of Laboratory Medicine, University Health Network, Toronto,, Ontario, Canada

    S H L George, A Milea, R Sowamber, A Tone & P A Shaw

  4. University of Toronto,, Toronto,, Ontario, Canada

    R Chehade, A Tone & P A Shaw

  5. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto,, Ontario, Canada

    P A Shaw

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Correspondence to P A Shaw.

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George, S., Milea, A., Sowamber, R. et al. Loss of LKB1 and p53 synergizes to alter fallopian tube epithelial phenotype and high-grade serous tumorigenesis. Oncogene 35, 59–68 (2016). https://doi.org/10.1038/onc.2015.62

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