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Estrogen receptor-positive mammary tumorigenesis in TGFα transgenic mice progresses with progesterone receptor loss

Oncogene volume 26, pages 5238–5246 (2007)Cite this article

Abstract

We characterized the novel NRL-transforming growth factor alpha (NRL-TGFα) transgenic mouse model in which growth factor - steroid receptor interactions were explored. The NRL promoter directs transgene expression to mammary ductal and alveolar cells and is nonresponsive to estrogen manipulations in vitro and in vivo. NRL-TGFα mice acquire proliferative hyperplasias as well as cystic and solid tumors. Quantitative transcript analysis revealed a progressive decrease in estrogen receptor alpha (ER) and progesterone receptor (PR) mRNA levels with tumorigenesis. However, ER protein was evident in all lesion types and in surrounding stromal cells using immunohistochemistry. PR protein was identified in normal epithelial cells and in very few cells of small epithelial hyperplasias, but never in stromal or tumor cells. Prophylactic ovariectomy significantly delayed tumor development and decreased incidence. Finally, while heterozygous (+/−) p53 mice did not acquire mammary lesions, p53+/− mice carrying the NRL-TGFα transgene developed ER negative/PR negative undifferentiated carcinomas. These data demonstrate that unregulated TGFα expression in the mammary gland leads to oncogenesis that is dependent on ovarian steroids early in tumorigenesis. Resulting tumors resemble a clinical phenotype of ER+/PR−, and when combined with a heterozygous p53 genotype, ER−/PR−.

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Acknowledgements

The authors greatly appreciate the assistance of Dr Donald Kundel, MD for histopathology evaluations, and Dr Lisa Arendt for critical manuscript reading. We also thank Chinghai Kao for graciously providing the PgRE construct. This work was supported by NIH grant K01-RR00145, University of Minnesota Medical Foundation (TARH), R01-CA64843 (EPS), R01-CA78312 (LAS), R01-CA58328 (MNG) and ES09090.

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Authors and Affiliations

  1. Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA

    T A Rose-Hellekant & E P Sandgren

  2. Department of Physiology and Pharmacology, University of Minnesota Medical School-Duluth, Duluth, MN, USA

    T A Rose-Hellekant, O Zhdankin & R Bolstad

  3. Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA

    M D Schroeder, J L Brockman & L A Schuler

  4. Department of Oncology, Medical School, University of Wisconsin-Madison, Madison, WI, USA

    K S Chen & M N Gould

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  1. T A Rose-Hellekant
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  2. M D Schroeder
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  3. J L Brockman
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  4. O Zhdankin
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Correspondence to T A Rose-Hellekant.

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Rose-Hellekant, T., Schroeder, M., Brockman, J. et al. Estrogen receptor-positive mammary tumorigenesis in TGFα transgenic mice progresses with progesterone receptor loss. Oncogene 26, 5238–5246 (2007). https://doi.org/10.1038/sj.onc.1210340

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  • DOI: https://doi.org/10.1038/sj.onc.1210340

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