Breast cancer is frequently characterized by hormonal control of its growth. Although significant levels of the estrogen receptor (ER) have been detected in more than 60% of human breast cancers, only two-thirds of these tumors respond to endocrine therapy. Following treatment with anti- estrogen or other endocrine therapy, these tumors also become hormone unresponsive. Loss of estrogen responsiveness is generally associated with loss of ER expression. This grant addresses the mechanism responsible for the loss of ER transcription and the role that endocrine treatment plays in the malignant progression of the disease from hormone dependent to a hormone independent phenotype. To address these questions, several studies were undertaken. Preliminary results from the first study suggest that the estrogen receptor represses ER gene transcription by a direct mechanism independent of protein synthesis. This effect appears to be mediated by a nERE in the promoter region of the receptor. New data in this submission suggests that the ER can bind to the nERE and repress transcription of a heterologous promoter. Data from the second study suggest that loss of ER expression in ER negative breast cancer cells is due to the presence of a tissue specific transcription repressor. New data tentatively identify a 65 kD protein which binds to the region of the ER promoter associated with repressor activity. In addition to the putative repressor, data are presented which suggest that estrogen receptor expression may also be controlled by a tissue specific enhancer.
The aims of this proposal are to: 1, define the role of the estrogen receptor in the repression of ER gene transcription in ER positive breast cancer and 2, define the mechanism responsible for loss of ER gene transcription in ER negative breast cancer. To achieve aim 1, experiments are designed to determine whether the repressor activity of the ER is due to a negative activity of the receptor the receptor. To define the mechanism responsible for loss of ER gene transcription in ER negative breast cancer (aim 2), the putative repressor will be isolated and ultimately cloned.
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