Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas

Cristina M. Contreras, Sushma Gurumurthy, J. Marshall Haynie, Lane J. Shirley, Esra A. Akbay, Shana N. Wingo, John O. Schorge, Russell R. Broaddus, Kwok Kin Wong, Nabeel Bardeesy, Diego H. Castrillon

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

Mutations in the LKB1 tumor suppressor gene result in the Peutz-Jeghers syndrome, an autosomal dominant condition characterized by hamartomatous polyps of the gastrointestinal tract and a dramatically increased risk of epithelial malignancies at other sites, including the female reproductive tract. Here we show that female mice heterozygous for a null Lkb1 allele spontaneously develop highly invasive endometrial adenocarcinomas. To prove that these lesions were indeed due to Lkb1 inactivation, we introduced an adenoviral Cre vector into the uterine lumen of mice harboring a conditional allele of Lkb1. This endometrial-specific deletion of the Lkb1 gene provoked highly invasive and sometimes metastatic endometrial adenocarcinomas closely resembling those observed in Lkb1 heterozygotes. Tumors were extremely well differentiated and histopathologically distinctive and exhibited alterations in AMP-dependent kinase signaling. Although Lkb1 has been implicated in the establishment of cell polarity, and loss of polarity defines most endometrial cancers, Lkb1-driven endometrial cancers paradoxically exhibit (given their highly invasive phenotype) normal cell polarity and apical differentiation. In human endometrial cancers, Lkb1 expression was inversely correlated with tumor grade and stage, arguing that Lkb1 inactivation or down-regulation also contributes to endometrial cancer progression in women. This study shows that Lkb1 plays an important role in the malignant transformation of endometrium and that Lkb1 loss promotes a highly invasive phenotype.

Original languageEnglish (US)
Pages (from-to)759-766
Number of pages8
JournalCancer Research
Volume68
Issue number3
DOIs
StatePublished - Feb 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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