title: Activation of integrin-ERBB2 signaling in undifferentiated thyroid cancer.
abstract: Undifferentiated thyroid carcinoma is one of the most aggressive human cancers. Although genetic changes underlying this aggressive cancer remain to be elucidated, RAS mutations have been frequently identified in it. Mice harboring a mutant thyroid hormone receptor Thrb(PV) (Thrb(PV/PV) ) spontaneously develop differentiated follicular thyroid carcinoma similar to human thyroid cancer. We recently demonstrated that targeting a RAS mutation (Kras(G12D) ) to the thyroid of Thrb(PV/PV) mice (Thrb(PV/PV) Kras(G12D) mice) promotes initiation and progression of undifferentiated thyroid cancer. To uncover genes destined to drive the aggressive cancer phenotype, we used cDNA microarrays to compare the gene expression profiles of thyroid cells of Kras(G12D) mice and thyroid tumor lesions of Thrb(PV/PV) and Thrb(PV/PV) Kras(G12D) mice. Analyses of microarray data identified 14 upstream regulators that were significantly altered in thyroid tumors of Thrb(PV/PV) and Thrb(PV/PV) Kras(G12D) mice. Most of these genes with altered expression function as key regulators in growth factor-induced signaling. Further analysis identified gene expression profiles of markedly elevated integrin levels, acting as upstream activators to stimulate ERBB2-mediated downstream signaling in thyroid tumors of Thrb(PV/PV) Kras(G12D) mice. The present studies uncovered integrin-activated ERBB2 signaling as one of the mechanisms in synergy between TRβPV and KRASG12D signaling to promote aggressive tumor growth in undifferentiated thyroid cancer.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Laboratory Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892.
authors.forename: Yuelin J
authors.initials: YJ
authors.lastname: Zhu
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Laboratory Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892.
authors.forename: Paul
authors.initials: P
authors.lastname: Meltzer
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892.
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
keywords: ERBB2; Growth regulation; gene expression; integrins; microarrays; thyroid cancer