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  • Original Paper
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Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations

Oncogene volume 24, pages 4220–4231 (2005)Cite this article

Abstract

The majority (75%) of human breast cancers express estrogen receptor (ER). Although ER-positive tumors usually respond to antiestrogen therapies, 30% of them do not. It is not known what controls the ER status of breast cancers or their responsiveness to antihormone interventions. In this report, we document that transgenic (TG) expression of Wnt-1 in mice induces ER-positive tumors. Loss of Pten or gain of Ras mutations during the evolution of tumors in Wnt-1 TG mice has no effect on the expression of ER, but overexpression of Neu or loss of p53 leads to ER-negative tumors. Thus, our results provide compelling evidence that expression of ER in breast cancer may be influenced by specific genetic changes that promote cancer progression. These findings constitute a first step to explore the molecular mechanisms leading to ER-positive or ER-negative mammary tumors. In addition, we find that ER-positive tumors arising in Wnt-1 TG mice are refractory to both ovariectomy and the ER antagonist tamoxifen, but lose ER expression with tamoxifen, suggesting that antiestrogen selects for ER-negative tumor cells and that the ER-positive cell fraction is dispensable for growth of these tumors. This is a first report of a mouse model of antiestrogen-resistant ER-positive breast cancers, and could provide a powerful tool to study the molecular mechanisms that control antiestrogen resistance.

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Acknowledgements

We thank Drs Jeff Rosen, Dan Medina, Kent Osborne, Adrian Lee, Steffi Oesterreich, Suzanne Fuqua, Craig Allred, Mike Lewis and Harold Varmus for stimulating discussions and/or critical review of this paper. In addition, we thank the Pathology Core Facility at the Breast Center for tissue processing and the Transgenic Mouse Facility at Baylor College of Medicine for animal husbandry. This work was supported in part by funds from Department of Defense (USAMRMC) BC030500 (to YL), SPORE (a developmental grant to YL) and National Institutes of Health GM47429 (to PC). KP was supported by a Cancer Research Institute fellowship award and by funds from National Institutes of Health P01 CA94060-02 and from the Martell Foundation awarded to her supervisor, Dr Harold Varmus. Some of the tumor samples used in this study were generated by YL when he was still a postdoctoral fellow in the laboratory of Dr Harold Varmus.

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Authors and Affiliations

  1. Breast Center, Baylor College of Medicine, One Baylor Plaza, N1210.03, Houston, TX, 77030, USA

    Xiaomei Zhang, Shixia Huang, Syed K Mohsin, Gary C Chamness, Rachel Schiff & Yi Li

  2. The Varmus Laboratory, Program in Cell Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021, USA

    Katrina Podsypanina

  3. Departments of Cell Biology and Dermatology, New York University School of Medicine, New York, NY, 10016, USA

    Sarah Hatsell & Pam Cowin

  4. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, N1210.03, Houston, TX, 77030, USA

    Yi Li

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Zhang, X., Podsypanina, K., Huang, S. et al. Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations. Oncogene 24, 4220–4231 (2005). https://doi.org/10.1038/sj.onc.1208597

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