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Ret Cooperates With Rb/P53 Inactivation in a Somatic Multi-Step Model For Murine Thyroid Cancer

  1. Author:
    Coxon, A. B.
    Ward, J. M.
    Geradts, J.
    Otterson, G. A.
    Zajackaye, M.
    Kaye, F. J.

  2. Author Address

    Kaye FJ NAVAL HOSP NCI BLDG 8-RM 5101 BETHESDA, MD 20889 USA NCI DEPT GENET BETHESDA, MD 20889 USA NATL NAVAL MED RES INST BETHESDA, MD 20889 USA DIV BASIC SCI ANIM SCI BRANCH VET & TUMOR PATHOL SECT FREDERICK, MD 21702 USA UNIV N CAROLINA DEPT LAB MED & PATHOL CHAPEL HILL, NC 27599 USA
    1. Year: 1998
  2. Journal: Oncogene
    1. 17
    2. 12
    3. Pages: 1625-1628
  4. Type of Article: Article
  1. Abstract:

    Mice bred to carry germline Rb and p53 null alleles are associated with a tumor spectrum that overlaps with the inherited multiple endocrine neoplasia-1 (MEN1) and MEN2 syndromes in humans, including medullary thyroid cancer (MTC). To study the genetic basis for these tumors, we microdissected MTC specimens or obtained fresh MTC tissue from nine independent Rb+/- p53(+/-) mice, amplified the region of the Ret gene known to be mutated in human MTC, and detected acquired missense Ret mutations in four different mice, These mutations were Localized to a group of tandem cysteines which are analogous to activating germline mutations observed in human MEN2A and familial MTC (FMTC), To determine whether the remaining wild type Rb allele was inactivated in these murine MTC samples, we subjected tumor tissue to immunohistochemical staining with an Rb antibody, and demonstrated the absence of RE staining in murine MTC, while normal tissue retained RE nuclear staining. These findings demonstrate the ability of the gene knockout model to recapitulate somatic multi-step tumorigenesis and suggest that the development of a murine neuroendocrine tumor requires mutational dysregulation within both receptor tyrosine kinase and nuclear tumor suppressor gene pathways. [References: 12]

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