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Cooperative induction of mammary tumorigenesis by TGFα and Wnts

Oncogene volume 19, pages 3193–3199 (2000)Cite this article

Abstract

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; (Shackleford and Varmus, 1988)). 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. Semi-quantitative 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.

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Acknowledgements

We are grateful to Gregory Shackleford for his generous gifts of the EH-2 and XC cell lines, env, gag, and Wnt-1 probes, as well as experimental protocols and advice. We also thank Ronald Swanstrom and Edison Liu for valuable advice, and the UNC Lineberger Comprehensive Cancer Center Biostatistics Core and Sean O'Brien for statistical analysis. This work was supported by NIH Grant CA61896 (to DC Lee). JA Schroeder was supported by NIH predoctoral training grant CA71341.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, 27599-7260, North Carolina, NC, USA

    Joyce A Schroeder, Kelly L Troyer & David C Lee

  2. Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, 27599-7260, North Carolina, NC, USA

    David C Lee

  3. UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, 27599-7260, North Carolina, NC, USA

    David C Lee

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Schroeder, J., Troyer, K. & Lee, D. Cooperative induction of mammary tumorigenesis by TGFα and Wnts. Oncogene 19, 3193–3199 (2000). https://doi.org/10.1038/sj.onc.1203652

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