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Mechanism of Action of a Novel Analog of Vitamin D3, 1alpha-hydroxy-24-ethyl Cholecalciferol (D5), in Normal and Transformed Human Breast Epithelial Cells

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Annual Summary rept. 1 May 2002-30 Apr 2003

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It is now well established that the active metabolite of vitamin D3, 1alpha,25OHsub 2Dsub 3, regulates cell growth and differentiation in various in vitro models. However, its clinical use is precluded due to its hyperglycemic activity in vivo. Hence, several less calcemic vitamin D3 analogs have been synthesized and evaluated for their chemopreventive and therapeutic efficacy in experimental carcinogenesis models. We have previously reported an analog of vitamin D3, 1-hydroxy-24-ethyl Cholecalciferol D5 to be antiproliferative and inducer of differentiation in carcinogen-transformed mouse mammary gland organ culture MMOC and breast cancer cells in vitro with little or no calcemic activity in vivo We transformed a normal breast epithelial cell line MCF-l2F to study the mechanism of action of D5 on the growth of normal vs transformed cell lines. Our results showed that D5 was effective in suppressing growth of carcinogen-transformed MCF-l2F cells and MMOC, while it does not affect the growth or morphology of normal MMOC or MCF-l2F cells. D5 also reduced the expression of EGF receptor in transformed MCF-l2F cells and decreased the invasiveness through the Matrigel coated membranes. Differential gene expression analysis indicated several genes that were altered by D5 treatment in the transformed cells including prohibitin and thioredoxin that were reported to be highly expressed in some tumor tissues. Breast cancer cells that were VDR as well as estrogen receptor positive ER, showed cell cycle arrest and apoptosis, while VDR but ER cells showed enhanced expression of various differentiation markers with D5 treatment. Transcription and expression of estrogen-inducible genes, progesterone receptor PR and trefoil factor 1 PS2, were significantly downregulated in ER BT-474 cells upon D5 treatment. This implies a differential effect of D5 on ER vs ER cells.

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  • Biochemistry
  • Medicine and Medical Research

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