title: Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice.
abstract: Mutations of BRAF are found in ∼45% of papillary thyroid cancers and are enriched in tumors with more aggressive properties. We developed mice with a thyroid-specific knock-in of oncogenic Braf (LSL-Braf(V600E)/TPO-Cre) to explore the role of endogenous expression of this oncoprotein on tumor initiation and progression. In contrast to other Braf-induced mouse models of tumorigenesis (i.e., melanomas and lung), in which knock-in of Braf(V600E) induces mostly benign lesions, Braf-expressing thyrocytes become transformed and progress to invasive carcinomas with a very short latency, a process that is dampened by treatment with an allosteric MEK inhibitor. These mice also become profoundly hypothyroid due to deregulation of genes involved in thyroid hormone biosynthesis and consequently have high TSH levels. To determine whether TSH signaling cooperates with oncogenic Braf in this process, we first crossed LSL-Braf(V600E)/TPO-Cre with TshR knockout mice. Although oncogenic Braf was appropriately activated in thyroid follicular cells of these mice, they had a lower mitotic index and were not transformed. Thyroid-specific deletion of the Gsα gene in LSL-Braf(V600E)/TPO-Cre/Gnas-E1(fl/fl) mice also resulted in an attenuated cancer phenotype, indicating that the cooperation of TshR with oncogenic Braf is mediated in part by cAMP signaling. Once tumors were established in mice with wild-type TshR, suppression of TSH did not revert the phenotype. These data demonstrate the key role of TSH signaling in Braf-induced papillary thyroid cancer initiation and provide experimental support for recent observations in humans pointing to a strong association between TSH levels and thyroid cancer incidence.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Aime T
authors.initials: AT
authors.lastname: Franco
authors.forename: Roberta
authors.initials: R
authors.lastname: Malaguarnera
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Liao
authors.forename: Emma
authors.initials: E
authors.lastname: Lundsmith
authors.forename: Shioko
authors.initials: S
authors.lastname: Kimura
authors.forename: Catrin
authors.initials: C
authors.lastname: Pritchard
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.forename: Terry F
authors.initials: TF
authors.lastname: Davies
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Ronald
authors.initials: R
authors.lastname: Ghossein
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Knauf
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
mesh_terms: D000818:Animals; D002277:Carcinoma; D002291:Carcinoma, Papillary; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D011863:Radioimmunoassay; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013972:Thyrotropin / Q000097:blood / Q000378:metabolism; D013974:Thyroxine / Q000097:blood / Q000378:metabolism
chemical_list: D019394:Ki-67 Antigen; D011989:Receptors, Thyrotropin; D013972:Thyrotropin; D007453:Iodide Peroxidase; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D013974:Thyroxine