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

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.

AFPep, a novel drug for the prevention and treatment of breast cancer, does not disrupt the estrous cycle or fertility in rats

“…5), as was previously reported (5,6,30). Although tamoxifen has been shown previously to decrease body mass significantly in rats (31,35), the absolute difference in body weight did not achieve statistical significance at any time. However, the growth rate of rats during treatment with tamoxifen (0.09 g/day) was significantly slower than the rate in the control group (0.455 g/day) p<0.04.…”

Differential effect of parity on rat mammary carcinogenesis after pre- or post-pubertal exposure to radiation

“…Rat mammary carcinomas exhibit a hormone dependency that is similar to that of human breast cancer. It has been reported that long-term tamoxifen treatment reduces the incidence of radiation-induced mammary cancer in rats 47 , suggesting that the hormonal environment greatly influences radiation-related mammary cancer risk. In the present study, the pre-pubertal exposure resulted in premature cessation of regular estrous cycling, like that observed for young female patients who received radiation therapy and experienced premature menopause 48 .…”

Application of High-Resolution1H MAS NMR Spectroscopy to the Analysis of Intact Bones from Mice Exposed to Gamma Radiation

“…Immediately after excision, the left femur from each mouse was fixed in 10% neutral buffered formalin for histopathological analysis using well-established methods (25, 26). Briefly, formalin-fixed femurs were demineralized in formic acid solution, washed, processed in an automated processor, embedded in paraffin, sectioned at 5 µm, mounted on glass microscope slides, and stained with hematoxylin and eosin.…”