The Role of the EGF Receptor and Vitamins A and D in Development and Progression of Breast Cancer to More Malignant Hormones Independent Phenotypes

Epidermal growth factor receptor (EGFR) is a strong prognostic indicator for poor survival rate independent of estrogen receptor status, suggesting that EGFR overexpression is an important step in the progression to estrogen independence. We have shown repression of EGFR mRNA and protein by 1,25-dih...

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Bibliographic Details
Main Author: Chrysogelos, Susan A
Format: Report
Language:English
Subjects:
Biochemistry
BREAST CANCER
CELLS(BIOLOGY)
DEOXYRIBONUCLEIC ACIDS
EGFR(EPIDERMAL GROWTH FACTOR RECEPTOR)
EPIDERMIS
ESTROGENS
GROWTH(PHYSIOLOGY)
HORMONES
MAMMARY GLANDS
MCF-7 CELLS
Medicine and Medical Research
PROTEINS
RIBONUCLEIC ACIDS
VDRE( VITAMIN D RESPONSE ELEMENT)
VITAMIN A
VITAMIN D
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Summary:Epidermal growth factor receptor (EGFR) is a strong prognostic indicator for poor survival rate independent of estrogen receptor status, suggesting that EGFR overexpression is an important step in the progression to estrogen independence. We have shown repression of EGFR mRNA and protein by 1,25-dihydroxyvitamin D3 In MCF7, T47D, and BT549 breast cancer cells. Functional mapping of the EGFR promoter in these cells has revealed a DNA segment between -536 and -478 that resembles a consensus vitamin D response element (VDRE) and confers a vitamin D response upon both the homologous and a minimal heterologous promoter. In vitro footprinting and gel shift assays have confirmed the binding of the vitamin D receptor (VDR) and an unknown partner to this putative VDRE. An sp1 binding site was also identified in close proximity and shown to bind sp1 from nuclear extract only when the VDRE is unoccupied. Mutational analysis and functional studies using a minimal heterologous promoter provide evidence that the VDR in concert with its unknown partner mediates EGFR repression through displacement of sp1. In BT549 cells these experiments also suggest that there are additional cell specific factors that allow the VDR to mediate repression of EGFR through low affinity VDRE half-sites at higher vitamin D concentrations. A model is proposed that accounts for these events at the molecular level.