Activating BRAF and PIK3CA mutations cooperate to promote anaplastic thyroid carcinogenesis.
Thyroid malignancies are the most common type of endocrine tumors. Of the various histologic subtypes, anaplastic thyroid carcinoma (ATC) represents a subset of all cases but is responsible for a significant proportion of thyroid cancer-related mortality. Indeed, ATC is regarded as one of the more aggressive and hard to treat forms of cancer. To date, there is a paucity of relevant model systems to critically evaluate how the signature genetic abnormalities detected in human ATC contribute to disease pathogenesis. Mutational activation of the BRAF protooncogene is detected in approximately 40% of papillary thyroid carcinoma (PTC) and in 25% of ATC. Moreover, in ATC, mutated BRAF is frequently found in combination with gain-of-function mutations in the p110 catalytic subunit of PI3'-Kinase (PIK3CA) or loss-of-function alterations in either the p53 (TP53) or PTEN tumor suppressors. Using mice with conditional, thyrocyte-specific expression of BRAF(V600E), we previously developed a model of PTC. However, as in humans, BRAF(V600E)-induced mouse PTC is indolent and does not lead to rapid development of end-stage disease. Here, we use mice carrying a conditional allele of PIK3CA to demonstrate that, although mutationally activated PIK3CA(H1047R) is unable to drive transformation on its own, when combined with BRAF(V600E) in thyrocytes, this leads to development of lethal ATC in mice. Combined, these data demonstrate that the BRAF(V600E) cooperates with either PIK3CA(H1074R) or with silencing of the tumor-suppressor PTEN, to promote development of anaplastic thyroid carcinoma.


CONCLUSIONS
This genetically relevant mouse model of ATC will be an invaluable platform for preclinical testing of pathway-targeted therapies for the prevention and treatment of thyroid carcinoma.
Authors' Affiliations: Helen Diller Family Comprehensive Cancer Center; Departments of Cell and Molecular Pharmacology, and roch-philippe.charles@ibmm.unibe.ch mcmahon@cc.ucsf.edu.
Roch-Philippe
RP
Charles
Authors' Affiliations: Helen Diller Family Comprehensive Cancer Center; Departments of Cell and Molecular Pharmacology, and.
Jillian
J
Silva
Pathology, University of California, San Francisco, California; and.
Gioia
G
Iezza
Surgical Oncology Laboratory, Sir Peter MacCallum Cancer Center, University of Melbourne, Victoria, Australia.
Wayne A
WA
Phillips
Authors' Affiliations: Helen Diller Family Comprehensive Cancer Center; Departments of Cell and Molecular Pharmacology, and roch-philippe.charles@ibmm.unibe.ch mcmahon@cc.ucsf.edu.
Martin
M
McMahon
D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D065646:Thyroid Carcinoma, Anaplastic / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human