Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy

Cristina M. Contreras, Esra A. Akbay, Teresa D. Gallardo, J. Marshall Haynie, Sreenath Sharma, Osamu Tagao, Nabeel Bardeesy, Masaya Takahashi, Jeff Settleman, Kwok Kin Wong, Diego H. Castrillon

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Endometrial cancer - the most common malignancy of the female reproductive tract - arises from the specialized epithelial cells that line the inner surface of the uterus. Although significant advances have been made in our understanding of this disease in recent years, one significant limitation has been the lack of a diverse genetic toolkit for the generation of mouse models. We identified a novel endometrial-specific gene, Sprr2f, and developed a Sprr2f-Cre transgene for conditional gene targeting within endometrial epithelium. We then used this tool to generate a completely penetrant Lkb1 (also known as Stk11)-based mouse model of invasive endometrial cancer. Strikingly, female mice with homozygous endometrial Lkb1 inactivation did not harbor discrete endometrial neoplasms, but instead underwent diffuse malignant transformation of their entire endometrium with rapid extrauterine spread and death, suggesting that Lkb1 inactivation was sufficient to promote the development of invasive endometrial cancer. Mice with heterozygous endometrial Lkb1 inactivation only rarely developed tumors, which were focal and arose with much longer latency, arguing against the idea - suggested by some prior studies - that Lkb1 is a haploinsufficient tumor suppressor. Lastly, the finding that endometrial cancer cell lines were especially sensitive to the mTOR (mammalian target of rapamycin) inhibitor rapamycin prompted us to test its efficacy against Lkb1-driven endometrial cancers. Rapamycin monotherapy not only greatly slowed disease progression, but also led to striking regression of pre-existing tumors. These studies demonstrate that Lkb1 is a uniquely potent endometrial tumor suppressor, but also suggest that the clinical responses of some types of invasive cancers to mTOR inhibitors may be linked to Lkb1 status.

Original languageEnglish (US)
Pages (from-to)181-193
Number of pages13
JournalDMM Disease Models and Mechanisms
Volume3
Issue number3-4
DOIs
StatePublished - Mar 2010

Fingerprint

Sirolimus
Endometrial Neoplasms
Tumors
Neoplasms
Genes
Ports and harbors
Cell Line
Gene Targeting
Cells
Endometrium
Transgenes
Uterus
Disease Progression
Epithelium
Epithelial Cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Neuroscience (miscellaneous)

Cite this

Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy. / Contreras, Cristina M.; Akbay, Esra A.; Gallardo, Teresa D.; Haynie, J. Marshall; Sharma, Sreenath; Tagao, Osamu; Bardeesy, Nabeel; Takahashi, Masaya; Settleman, Jeff; Wong, Kwok Kin; Castrillon, Diego H.

In: DMM Disease Models and Mechanisms, Vol. 3, No. 3-4, 03.2010, p. 181-193.

Research output: Contribution to journalArticle

Contreras, CM, Akbay, EA, Gallardo, TD, Haynie, JM, Sharma, S, Tagao, O, Bardeesy, N, Takahashi, M, Settleman, J, Wong, KK & Castrillon, DH 2010, 'Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy', DMM Disease Models and Mechanisms, vol. 3, no. 3-4, pp. 181-193. https://doi.org/10.1242/dmm.004440
Contreras, Cristina M. ; Akbay, Esra A. ; Gallardo, Teresa D. ; Haynie, J. Marshall ; Sharma, Sreenath ; Tagao, Osamu ; Bardeesy, Nabeel ; Takahashi, Masaya ; Settleman, Jeff ; Wong, Kwok Kin ; Castrillon, Diego H. / Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy. In: DMM Disease Models and Mechanisms. 2010 ; Vol. 3, No. 3-4. pp. 181-193.
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