IDENTIFICATION OF ERES IN THE AMPHIREGULIN GENE

描述（申请人描述）：

DESCRIPTION (Applicant's Description): The main goal of the applicant during this award period is to develop the skills and the ability to become a productive, independent investigator able to obtain continuous funding to support her own research program. She anticipates that the research foundation she will develop in Dr. Maihle's laboratory will result in future collaborative interactions as well. These skills will be developed through the participation in: hands-on workshops in molecular biology techniques, journal clubs, seminars, scientific meetings, and through the interaction with other scientists in the field. The Tumor Biology Program at the Mayo Clinic, MN provides her with an outstanding academic environment to accomplish this goal. The proposed research study will provide her the opportunity to master the commonly used research approaches in tumor biology. Breast carcinoma, one of the most common cancers in women, may have both its genesis and growth influence by hormonal factors. Patient's hormonal environment has been shown to affect the clinical course of breast cancer. The effect of estrogen in the stimulation of cell growth in breast cancer cell lines depends on the presence of active functional estrogen receptors. Moreover, the loss of estrogen receptor responsiveness is associated with hormone growth independence in breast cancer cell lines, and with malignant progression and poor prognosis. The mechanism of estrogen action in growth stimulation is poorly understood. However, it has been postulated that estrogen may act, at least in part, through the endogenous production of growth factors that may function in an autocrine/paracrine or juxtacrine manner. In Dr. Maihle's laboratory, it has been demonstrated that one GF/GFR circuit is regulated by both estrogen and androgen, i.e., the a m phiregulin/epidermal growth factor receptor pathway (AR/EGFR). The synthesis of these gene products has been shown to be regulated at both mRNA and protein levels. Dr. Maihle and others have shown that regulation of the EGFR synthesis occurs at the transcriptional level. In addition, it has been r e p orted that estrogen stimulates the induction of AR mRNA at the transcriptional level in estrogen responsive cells. In this application the applicants propose to test the hypothesis that the mechanism of AR induction by steroid hormones occurs at the transcriptional level and that the action of steroids in the regulation of breast carcinoma cell growth is through the AR/EGFR pathway. To test this hypothesis they propose to determine the kinetics of induction of EGFR, AR, and TGF-alpha mRNAs by estrogen in breast carcinoma cells and to identify and characterize the estrogen response elements in the AR gene.