Environmental Factor, March 2010, National Institute of Environmental Health Sciences
Estrogen Receptors and Tumor Development
By Omari J. Bandele
On Feb. 4, NIEHS Principal Investigator Kenneth Korach, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/lrdt/receptor/index.cfm), presented a talk on "Estrogen Receptors: Are They Involved in Tumorigenesis and Toxicity?" to a capacity audience of trainees and fellow principal investigators. The lecture was part of the Laboratory of Molecular Carcinogenesis Seminar Series.
Korach's research involves using mouse models to assess the contribution of estrogen receptor (ER) alpha and beta in tumorigenesis and hormone-induced toxicity. According to him, a better understanding the role of ERs could help researchers develop targeted therapies for a range of ER-linked diseases.
During his talk, Korach, who is chief of the Laboratory of Reproductive and Developmental Toxicology within the NIEHS Environmental Disease and Medicine Program, emphasized that most female and male organ systems - including the reproductive, immune, and cardiovascular - express ERs and have estrogenic activity. He also explained that many environmental chemicals have estrogenic and other hormonal activity that can induce toxic effects.
Mice lacking estrogen receptors recapitulate clinical conditions
To evaluate the contribution of the ERs to tumorigenesis and hormone toxicity, Korach and colleagues generated estrogen receptor knockout (ERKO) mice that lack ER alpha (alpha ERKO) or beta (beta ERKO). These animals demonstrated for the first time that loss of ER activity is not lethal.
According to Korach, the ERKO mice are infertile, insulin resistant, and obese, and they experience bone loss - conditions also described in a patient lacking ER activity. "These results demonstrate that ERKO mice are good experimental systems to explore clinical conditions due to loss of ER activity," he contends. "This system allows one to appreciate how alterations in hormone signaling can modify the function of several organ systems."
WNT-ERKO mice clarify ER involvement in tumor progression
Breast cancer affects individuals throughout the world, and Korach believes ERKO mice will help to further understand the role estrogen receptors play in mammary tumorigenesis.
Some mammary tumors develop in the absence of receptor activity - a type known as hormone resistant - and are unresponsive to anti-hormone therapy such as tamoxifen. This mouse model provides a unique opportunity to study the biology of hormone-resistant tumorigenesis and progression.
To define the role of estrogen receptors in mammary tumorigenesis, Korach led a collaborative study with Harold Varmus, M.D., former NIH director. In this study, ERKO mice were crossed with transgenic mice that develop mammary tumors due to expression of the Wnt-1 oncogene. While WNT-ERKO mice developed Wnt-1-induced tumors in the absence of the ER, they experienced a delay in tumorigenesis. Although this study suggests that the receptor does not contribute to the initiation of mammary tumors, Korach highlighted that it indicates a role for the ER in tumor progression.
ER alpha and beta contribute to hormone-induced toxicity
After years on the market, the prescription drug Diethylstilbestrol (DES) was found to be a toxic synthetic estrogenic compound. Korach and colleagues sought to determine whether estrogen receptors mediate the toxicity of DES. They evaluated the effect of DES exposure in female ERKO mice and observed that wild-type animals exhibited a high incidence of uterine lesions, whereas alpha ERKO mice had no abnormal growths. This finding led Korach to believe ER alpha-mediated regulation of HOX gene expression - involved in reproductive tract development - may contribute to the toxic effects of DES.
Korach concluded by illustrating that male mice are also susceptible to the toxic effects of DES. Exposure to DES suppressed seminal vesicle development and gene reprogramming in wild-type and beta ERKO mice - while alpha ERKO mice were protected. These results suggest ER alpha mediates DES-induced toxicity in female and male mice.
Korach said he hopes these mice will provide a unique opportunity to determine whether estrogen can act as a carcinogen in the absence of the estrogen receptor - an important question for cancer biologists in the field of hormonal carcinogenesis as they search for ways to control tumor proliferation.
(Omari J. Bandele, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Environmental Genomics Group.)