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Carcinogenesis Advance Access published online on April 28, 2005
Carcinogenesis, doi:10.1093/carcin/bgi103
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received April 2, 2004
Revised January 31, 2005
Accepted April 16, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Tamoxifen resistance and Her2/neu expression in an aged, irradiated rat breast carcinoma model

Norman C. Peterson 1*, Matthew D. Servinsky 1, Archie Christian 1, Zhongsheng Peng 1, Weiping Qiu 1, Jill Mann 1, John Dicello 1, and David L. Huso 1

1 Department of Comparative Medicine, Johns Hopkins University, 733 N. Broadway, Baltimore, MD 21205

* To whom correspondence should be addressed.
Norman C. Peterson, E-mail: npeterso{at}jhmi.edu


  Abstract

Clear links have been established between occupational or therapeutic radiation exposure and breast cancer. Tamoxifen chemoprevention following radiation exposure may be able to reduce the risk of developing breast cancer later in life. In order to model carcinogenesis in this setting, an in vivo model of tamoxifen chemoprevention and tamoxifen failure in a radiation-induced rat mammary carcinoma model was characterized. Two hundred twenty-seven 60 day old female rats received whole body or sham exposure to ionizing radiation . Thirty days later long-term, continuous, tamoxifen chemoprevention was initiated in half the population and all animals were monitored over three and a half years for the development of mammary tumors. Mammary tumors were surgically removed and carcinomas were histologically identified and characterized. Results showed that tamoxifen chemoprevention decreased the incidence and prolonged the latency of radiation-induced mammary carcinomas. However, many individuals receiving tamoxifen chemoprevention developed their first carcinoma very late in life. These carcinomas shared morphological features distinct from the majority of carcinomas that developed in the absence of tamoxifen chemoprevention. Analyses of cell lines established from these carcinomas and immunohistochemisty of tumor sections revealed that the highest levels of Her2/neu expression were associated with in vivo tamoxifen exposure. Treatment of rat mammary carcinoma cells with an anti-rat Her2/neu monoclonal antibody (MAb 7.16.4) inhibited cell growth and this effect was more pronounced in the presence of tamoxifen. These studies suggest that carcinoma growth driven by the Her2/neu pathway may be associated with tamoxifen chemoprevention failure in the rat mammary carcinoma model. Additionally, strategies combining targeted Her2/neu antibodies, vaccines, or drugs with estrogen pathway modification may be more effective in reducing breast cancer chemoprevention failures.

Keywords: Cancer Treatment; Animal Model; Estrogen; Tyrosine Kinase; Herceptin.
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