Effect of 1,25-dihydroxyvitamin D3 on mouse mammary tumor (GR) cells: evidence for receptors, cellular uptake, inhibition of growth and alteration in morphology at physiologic concentrations of hormone.
Mammary glands are target tissues for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). We have examined a mouse mammary tumor cell line (GR) for receptors of 1,25(OH)2D3 and have examined alterations in the growth and morphology of these cells in response to 1,25(OH)2D3. GR cells contain a high affinity (Kd approximately 10(-11)), low-capacity receptor with a high specificity for 1,25(OH)2D3. The 1,25(OH)2D3 receptor in GR cells has a sedimentation coefficient of 3.5 and elutes from DEAE cellulose columns with approximately 0.15 M KCl. These properties of the receptor are similar to those reported for other 1,25(OH)2D3 receptors. 1,25(OH)2D3 is internalized by GR cells in situ and specifically bound 1,25(OH)2D3 is found predominantly, if not entirely, in the nucleus as determined by cell fractionation and autoradiographic techniques. The incubation of GR cells in culture for 7 days with 1,25(OH)2D3 markedly alters cell growth. Cell growth is retarded in a dose-dependent manner; physiologic concentrations (10(-10) M) of 1,25(OH)2D3 retard cell growth by approximately 50%. In addition, GR cells incubated with 10(-9) to 10(-8) M 1,25(OH)2D3 undergo marked morphological changes. The incubation of GR cells with other vitamin D metabolites such as 25-hydroxyvitamin D3 (25(OH)D3) at a concentration of 10(-9) M does not significantly alter cell growth or morphology. The presence of high affinity receptors for 1,25(OH)2D3, the specific internalization of 1,25(OH)2D3 predominantly into the nuclei, and the significant effects of physiological concentrations of 1,25(OH)2D3 on cell growth suggest a direct, specific, nuclear effect of 1,25(OH)2D3 on GR cells. The mouse mammary tumor model might be useful in examining the effect of 1,25(OH)2D3 on tumor formation.
Gross
M
M
Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905.
Kost
S B
SB
Ennis
B
B
Stumpf
W
W
Kumar
R
R
D000818:Animals; D001345:Autoradiography; D002117:Calcitriol / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002499:Centrifugation, Density Gradient; D002848:Chromatography, DEAE-Cellulose; D003600:Cytosol; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000302:isolation & purification*; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D002117:Calcitriol