A large percentage of estrogen receptor (ER) positive breast cancers fail to respond to antiestrogen therapy. Although the reason for their hormone resistance is unknown, subpopulations of tumor cells, with abnormal responses to antiestrogens, are being identified. Furthermore, these phenomena are associated with the end stages of the disease. Cooperative ER-transcription factor interactions, such as those between the ER and the fos-jun oncoproteins in the AP1 complex (which appear to depend on hormone may play a role in these inappropriate responses. These investigations will examine the role of certain carcinostatic A-ring substituted estrogens in the aberrant regulation of distal promoter elements on the pS2 breast cancer gene. Toward this goal, we will: (1) examine the potential for cross-talk between the ER and AP1 by transient transfection of the pS2tkCAT fusion gene into MCF 7 cells, using estrogens and A-ring analogues of estrogen; (2) we will use receptor mutants aided by protein prediction programs to test the hypothesis that ER-mediated gene expression, recently shown to vary with the location of the electronegative isopotential on the A-ring of these analogues, relies on the integrity of the hormone-dependent transcription activation function (AF 2) of the ER; and, (3) compare these results with those obtained in an in vitro transcription assay system, also using analogue- occupied ER and mutants.
| Brooks, Sam C; Skafar, Debra F (2004) From ligand structure to biological activity: modified estratrienes and their estrogenic and antiestrogenic effects in MCF-7 cells. Steroids 69:401-18 |
| Liu, G; Schwartz, J A; Brooks, S C (2000) Estrogen receptor protects p53 from deactivation by human double minute-2. Cancer Res 60:1810-4 |
| Liu, G; Schwartz, J A; Brooks, S C (1999) p53 down-regulates ER-responsive genes by interfering with the binding of ER to ERE. Biochem Biophys Res Commun 264:359-64 |
| Schwartz, J A; Brooks, S C (1998) Changes in the structure of the ligand or substitutions to AF2 residues in the estrogen receptor make independent contributions to coactivator sensitivity by SRC-1. J Steroid Biochem Mol Biol 67:223-32 |
| Schwartz, J A; Brooks, S C (1997) Neutral mutations to three acidic AF2 residues in the mouse estrogen receptor confer agonist activity to A-ring isomers of estradiol. J Steroid Biochem Mol Biol 62:173-84 |
