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Identification of Oncogenes Cooperating in Murine Mammary Tumorigenesis

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Annual summary rept. 1 Jun 2001-31 May 2002

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In order to identify and characterize additional novel or unexpected proto-oncogenes that, in addition to fibroblast growth factors Fgfs cooperate with Wntl in murine mammary tumorigenesis, we have generated MMTV-infected Wnt10bFgfr2DN, WntlFgfr2DN and WntlFgP bitransgenic mice. In the first two models, the Wnt oncogenic signal is constitutively overexpressed in their mammary gland, cooperative oncogenic Fgf signals should be abolished by the expression of a dominant-negative FOF receptor Fgfr2DN The WntlFgf3 model displays constitutive overexpression of both Wnt and Fgfoncogenic signals. In all three models, only those cells carrying MMTV-insertionally activated cellular proto-oncogenes, other than Wnts and Fgfs, should have a growth advantage in the bitransgenic mammary gland. The clonal expansion of these cells leads to mammary tumorigenesis. As proposed, we have generated cohorts of 20-25 MMTV-infected Wnt1ObFgfr2DN, Wnt1Fgfr2DN and WntlFgf3 bitransgenic females. As controls, we have also generated uninfected bitransgenic cohort, as well as MMTV-infected and uninfected monotrausgenic female control groups. To date, multiple mammary adenocarcinomas have appeared in the MMTV-infected bitransgenic animals. These tumors appeared with a mean latency of 5.4 and 3 months in WntlFgfr2DN and Wnt1Fgf3 females respectively. Wnt1ObFgfr2DN tumor histopathology corresponded to papillary lobular, ductal, and metaplastic invasive carcinomas. Wnt1Fgfr2DN tumors were mainly papillary carcinomas, and Wnt1Fgf3 tumors displayed features of highly metastatic to lungs papillary carcinomas. At least 1OWntlObFgfr2DN, 6WntlFgfr2DN and 1 Wnt1Fgf3 tumors carry newly integrated MMTV proviruses. Our current efforts are to clone and identify these genes, and we are also screening for additional candidate tumors.

Subject Categories:

  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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