Cooperative induction of mammary tumorigenesis by TGFalpha and Wnts.
We previously reported that multiparous WAP-TGFalpha transgenic mice develop mammary gland carcinomas with complete incidence. TGFalpha-induced tumors appear stochastically and with relatively long latency, indicating an additional requirement for other genetic alterations. To identify genes that cooperate with TGFalpha in mammary tumorigenesis, we used a retroviral insertion approach featuring a cloned and infectious hybrid MMTV (C3H/Mtv-1; (Shackleford and Varmus, 1988)). Tumor latency was decreased approximately 30% in MMTV-infected WAP-TGFalpha transgenic animals compared to noninfected 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-TGFalpha tumors, and some noninfected WAP-TGFalpha 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 (TGFalpha) and Wnt growth factors.
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill 27599-7260, USA.
J A
JA
Schroeder
K L
KL
Troyer
D C
DC
Lee
D000818:Animals; D001665:Binding Sites; D002461:Cell Line, Transformed; D004247:DNA; D005260:Female; D015870:Gene Expression; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D016662:Virus Integration; D051153:Wnt Proteins; D051155:Wnt1 Protein; D060508:Wnt3 Protein; D029961:Zebrafish Proteins
D008894:Milk Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016211:Transforming Growth Factor alpha; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D060508:Wnt3 Protein; C555508:Wnt3 protein, mouse; D029961:Zebrafish Proteins; C024471:whey acidic proteins; D004247:DNA