| Although development of a normal functioning human mammary gland is dependent upon estrogens, lifetime exposure to estrogens is also one of the major risk factors for the development of breast cancer. The mechanism(s) for the development of breast cancer by estrogens are not fully defined. One likely mechanism is through estrogen binding to estrogen receptor (ER), resulting in transcriptional activation or repression of estrogen regulated genes involved in breast tumor initiation and/or progression. Therefore, the estrogen receptor is one of the major therapeutic targets for breast cancer treatment. Antiestrogens, like tamoxifen, have been used successfully in the treatment and prevention of breast cancer. Although antiestrogens are useful, approximately 33% of breast tumors are estrogen receptor negative and therefore unresponsive to antiestrogen therapies. Furthermore, many breast tumors become tamoxifen resistant and physiologically respond to tamoxifen like estrogens. For these reasons, a further understanding of the role of estrogens and ER in breast cancer development and/or progression is necessary.; The goal of this thesis was to identify ERalpha interacting proteins in yeast two-hybrid screenings in order to further define the mechanism(s) behind estrogen- and ER-mediated breast cancer initiation and/or progression . The screenings resulted in the identification of a novel gene, E&barbelow;strogen D&barbelow;own-regulated G&barbelow;ene 1 (EDG1). Studies presented in chapter III indicate that ER directly down-regulates the expression of EDG1 mRNA and protein, EDG1 is lost in the majority of breast tumors, and EDG1 can inhibit breast cell proliferation (Wittmann et al., 2003). These data suggest that down-regulation of EDG1 provides a novel pathway for the role of estrogens and ER in breast cancer. A link between ERalpha and EDG1 is further demonstrated in chapter IV, where EDG1 is shown to inhibit ERalpha transcriptional activity independent of the interaction between EDG1 and ERalpha (Wittmann and Montano, [submitted for publication]). In Chapter V, preliminary data on additional EDG1 interacting proteins will be presented. Studies will also be presented that suggest EDG1 may be involved in prostate tumorigenesis and possibly undergoes genetic alterations in breast tumors, although further studies are necessary to confirm these findings. |
