Cooperative induction of mammary tumorigenesis by TGFα and Wnts

We previously reported that multiparous WAP-TGFα transgenic mice develop mammary gland carcinomas with complete incidence. TGFα-induced tumors appear stochastically and with relatively long latency, indicating an additional requirement for other genetic alterations. To identify genes that cooperate with TGFα in mammary tumorigenesis, we used a retroviral insertion approach featuring a cloned and infectious hybrid MMTV (C3H/Mtv-1). Tumor latency was decreased approximately 30% in MMTV-infected WAP-TGFα transgenic animals compared to non-infected transgenic controls, and > 30% of the corresponding tumors displayed evidence of integrated C3H/Mtv-1 DNA. PCR-based analyses of DNAs from two virus-infected, transgenic tumors revealed integration of hybrid MMTV in 3' untranslated exons of the Wnt-1 or Wnt-3 oncogenes. Moreover, Northern blots confirmed dramatic induction of Wnt-1 or Wnt-3 transcripts in the respective tumors, indicating that MMTV integration resulted in activated expression of these genes. Semiquantitative RT-PCR analyses showed that overexpression of Wnt-1 or Wnt-3 was a common occurrence in MMTV-infected WAP-TGFα tumors, and some non-infected WAP-TGFα tumors also showed evidence of elevated Wnt-3 transcripts. Collectively, these results reveal cooperative induction of mammary gland tumorigenesis by simultaneous deregulation of EGF-like (TGFα) and Wnt growth factors.