Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform Thyroid epithelial cells in vivo

Kelly A. Miller, Nicole Yeager, Kristen Baker, Xiao Hui Liao, Samuel Refetoff, Antonio Di Cristofano

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Thyroid tumors arising from the follicular cells often harbor mutations leading to the constitutive activation of the P13K and Ras signaling cascades. However, it is still unclear what their respective contribution to the neoplastic process is, as well as to what extent they interact. We have used mice harboring a Kras oncogenic mutation and a Pten deletion targeted to the thyroid epithelium to address in vivo these questions. Here, we show that although each of these two pathways, alone, is unable to transform thyroid follicular cells, their simultaneous activation is highly oncogenic, leading to invasive and metastatic follicular carcinomas. In particular, phosphatidylinositol-3-kinase (PI3K) activation suppressed Kras-initiated feedback signals that uncouple mitogenactivated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activation, thus stunting MAPK activity; in addition, PI3K and Kras cooperated to drastically up-regulate cyclin Dl mRNA levels. Finally, combined pharmacologic inhibition of PI3K and MAPK completely inhibited the growth of double-mutant cancer cell lines, providing a compelling rationale for the dual targeting of these pathways in thyroid cancer.

Original languageEnglish (US)
Pages (from-to)3689-3694
Number of pages6
JournalCancer Research
Volume69
Issue number8
DOIs
StatePublished - Apr 15 2009

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Phosphatidylinositol 3-Kinase
Extracellular Signal-Regulated MAP Kinases
Protein Kinases
Thyroid Gland
Growth Disorders
MAP Kinase Kinase Kinases
Neoplastic Processes
Mutation
Cyclins
Thyroid Neoplasms
Neoplasms
Up-Regulation
Epithelium
Carcinoma
Cell Line
Messenger RNA
Growth
Thyroid Epithelial Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform Thyroid epithelial cells in vivo. / Miller, Kelly A.; Yeager, Nicole; Baker, Kristen; Liao, Xiao Hui; Refetoff, Samuel; Di Cristofano, Antonio.

In: Cancer Research, Vol. 69, No. 8, 15.04.2009, p. 3689-3694.

Research output: Contribution to journalArticle

Miller, Kelly A. ; Yeager, Nicole ; Baker, Kristen ; Liao, Xiao Hui ; Refetoff, Samuel ; Di Cristofano, Antonio. / Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform Thyroid epithelial cells in vivo. In: Cancer Research. 2009 ; Vol. 69, No. 8. pp. 3689-3694.
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