2002 WHRG Grant Program

Faculty

Grant Program
- Application Form
- Application Guidelines
- Grant Recipients

Symposia

Estrogen Receptor Signaling and Vascular Endothelial Growth Factor
Armina A. Kazi
School of Medicine, University of Maryland, Baltimore

Estrogen plays a major role in morphological changes that the uterus undergoes during a menstrual cycle; it also affects breast tissue development and differentiation. It is believed that estrogen elicits its effects on target tissues in part via vascular endothelial growth factor (VEGF), which has been linked to increased vascular permeability, edema, and angiogenesis. Expression levels and localization of VEGF mRNA and protein has been shown to change throughout the human menstrual cycle and rat estrous cycle in estrogen target tissues. Studies conducted in this laboratory and others suggest that the estrogen 17b-estradiol (E₂) increases VEGF mRNA expression by upregulating gene transcription. Interestingly, the selective estrogen receptor (ER) modular tamoxifen (TAM), which has been demonstrated to have antiestrogenic effects, increases VEGF gene transcription similar to E₂. The signal transduction mechanisms by which E₂ and TAM are acting remain inconsistent and unclear. Thus, using MCF-7 breast cancer cells as a cellular model of estrogen receptor signaling in general, the overall aim of this proposal is to investigate the similarities and differences of E₂ and TAM-mediated pathways regulating VEGF mRNA induction. Specific aims are (1) to identify ERa and/or ERb binding regions on the VEGF promoter after E₂ and TAM treatment, (2) to determine the temporal relationship between ER association with the VEGF promoter and VEGF transcription, (3) to identify the specific response elements involved, (4) to assess the degree to which VEGF transcription is regulated by the organization of the VEGF promoter, and (5) to identify the coregulator proteins recruited to the VEGF promoter by E₂- and TAM-liganded ERs. Results obtained from the proposed experiments will provide a better understanding of estrogenic regulation of VEGF expression and also of estrogen receptor signaling in general. This research will, in turn, have important implications in understanding the normal physiology of steroid hormone-regulated tissues (i.e., uterus and breast) and in the development of therapeutic approaches to treating pathophysiological conditions in these tissues.