Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy.
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.
Department of Pathology, UT Southwestern Medical Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Cristina M
CM
Contreras
Esra A
EA
Akbay
Teresa D
TD
Gallardo
J Marshall
JM
Haynie
Sreenath
S
Sharma
Osamu
O
Tagao
Nabeel
N
Bardeesy
Masaya
M
Takahashi
Jeff
J
Settleman
Kwok-Kin
KK
Wong
Diego H
DH
Castrillon
D055372:AMP-Activated Protein Kinases; D000818:Animals; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D019426:Integrases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009928:Organ Specificity / Q000187:drug effects; D019683:Penetrance; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases
D055233:Cornified Envelope Proline-Rich Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C491982:Sprr2f protein, mouse; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C045073:Cre recombinase; D019426:Integrases; D020123:Sirolimus