Cooperative induction of mammary tumorigenesis by TGF alpha and Wnts

We previously reported that multiparous WAP-TGF alpha transgenic mice devel op mammary gland carcinomas with complete incidence, TGF alpha-induced tumo rs appear stochastically and with relatively long latency, indicating an ad ditional requirement for other genetic alterations, To identify genes that cooperate with TGF alpha in mammary tumorigenesis, we used a retroviral ins ertion approach featuring a cloned and infectious hybrid MMTV (C3H/Mtv-1; ( Shackleford and Varmus, 1988)), Tumor latency,vas decreased approximately 3 0% in MMTV-infected WAP-TGF alpha transgenic animals compared to noninfecte d transgenic controls, and >30% of the corresponding tumors displayed evide nce of integrated C3H/Mtv-1 DNA, PCR-based analyses of DNAs from two virus- infected, transgenic tumors revealed integration of hybrid MMTV in 3' untra nslated exons of the Wnt-1 or Wnt-3 oncogenes, Moreover, Northern blots con firmed dramatic induction of Wnt-1 or Wnt-3 transcripts in the respective t urners, indicating that MMTV integration resulted in activated expression o f these genes, Semi-quantitative RT-PCR analyses showed that overexpression of Wnt-1 or Wnt-3 was a common occurrence in MMTV-infected WAP-TGF alpha t umors, and some noninfected WAP-TGF alpha tumors also shelved evidence of e levated Wnt-3 transcripts, Collectively, these results reveal cooperative i nduction of mammary gland tumorigenesis by simultaneous deregulation of EGF -like (TGF alpha) and Wnt growth factors.