We have found that some progestins commonly used in contraceptives activate ER in a manner comparable to E2. One structural difference between the estrogenic progestins and progesterone (which lacks estrogenic activity) is the absence of a 19 methyl group. We originally hypothesized that the 19-position was important for estrogenic action, but we have recently found that the presence or absence of a 19 methyl group does not determine the estrogenic action of progestins. Current evidence suggests that the free hydroxyl group at the 17-position more accurately determines the estrogenic activity of progestins.

Because structural changes in ligand can result in greater estrogenic action, we hypothesized that alterations in ER may increase the estrogenic activity of antiestrogens that are partial agonists. We examined tumors which proliferate in the presence of TAM, and have identified an ER mutation in one tumor line. A TAM analogue and keoxifene (another antiestrogen) can activate this mutant ER, stimulating transcription and altering proliferative rate of breast cancer cells. Neither antiestrogen can activate the wild type ER. These results are the first description of a naturally occurring ER mutation which can increase the estrogenicity of antiestrogens and suggests a mechanism for TAM stimulated tumor growth.

ER binds to DNA at a site known as the estrogen response element (ERE), and this interaction is a further mechanism of transcriptional regulation. We have found that increasing the number of tandem ERE's increases the estrogenic activity of a TAM analogue. Furthermore, current dogma on ERE's states that the sequence of the central base pairs do not influence enhancer activity. We find, however, that ERE activation by ER is modulated by the specific sequence of these 'spacer' base pairs. The findings presented in this thesis further our understanding of ligand-dependent transcription factor interactions and ER mediated signal transduction.

• Levenson AS, Wolf DM, Catherino WH, Takei H, Jordan VC. Understanding the antiestrogenic actions of Raloxifene and a mechanism of drug resistance to tamoxifen. Breast Cancer 5:99-106, 1998.
• Levenson AS, Catherino WH, Jordan VC. Estrogenic activity is increased for an antiestrogen by a natural mutation of the estrogen receptor. J Steroid Biochem Molec Biol 60:261-268, 1997.
• Catherino WH, Jordan VC. Nomegestrol acetate, a clinically useful 19-norprogesterone derivative which lacks estrogenic activity. J Steroid Biochem Mol Biol 55:239-246, 1995.
• Catherino WH, Wolf DM, Jordan VC. A naturally occurring estrogen receptor mutation results in increased estrogenicity of a tamoxifen analog. Mol Endocrinol 9:1053-1063, 1995.
• Jordan VC, Catherino WH, Wolf DM. A mutant receptor as a mechanism of drug resistance to tamoxifen treatment. Ann N Y Acad Sci 761:138-147, 1995.
• Catherino WH, Jordan VC. Increasing the number of tandem estrogen response elements increases the estrogenic activity of a tamoxifen analogue. Cancer Lett 92:39-47, 1995.
• Catherino WH, Jordan VC. The biological action of cDNAs from mutated estrogen receptors transfected into breast cancer cells. Cancer Lett 90:35-42, 1995.
• Catherino WH, Jordan VC. A risk-benefit assessment of tamoxifen therapy. Drug Saf 8:381-397, 1993.
• Jordan VC, Jeng MH, Catherino WH, Parker CJ. The estrogenic activity of synthetic progestins used in oral contraceptives. Cancer 71:1501-1505, 1993.
• Catherino WH, Jeng MH, Jordan VC. Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism. Br J Cancer 67:945-952, 1993.