Antiestrogen potentiation of antiproliferative effects of vitamin D3 analogues in breast cancer cells.
[3H]thymidine incorporation and DNA content were used to investigate the antiproliferative effects of 1,25(OH)2D3 and four analogues [16-ene-1,25(OH)2D3 (16-ene)]; 16-ene,23-yne-1,25(0H)2,D3; EB1089; and 22 oxa-1,25(OH)2D3] on MCF-7, BT-474, and MDA-MB-453 breast cancer cell lines. 1,25(OH)2D3 and the analogues elicited a biphasic response from MCF-7 and BT-474 estrogen receptor (ER)-positive cells, in the presence of estradiol (E2), with lower doses (between 10(-12) and 10(-10) M) tending to stimulate proliferation and higher doses (between 10(-9) and 10(-6) M) inhibiting proliferation by as much as 65%. In the absence of E2, the stimulatory effect was abrogated. Proliferation of MDA-MB-453, estrogen receptor-negative (ER-) cells, was stimulated by these compounds only at 10(-12) M, and inhibited by all higher doses, by as much as 83%. All three cell lines were shown to be vitamin D receptor (VDR) positive, and 1,25(OH)2D3 and all four analogues bound to the VDR with high affinities in each cell line. The antiestrogen ICI 164,384 inhibited the proliferation of all three cell lines. ICI 164,384 at 10(-8) M in combination with 1,25(OH)2D, or EB1089 converted biphasic response of the ER+ cells to one resembling the response of the ER- cells, by eliminating the stimulatory response elicited by 1,25(OH)2D3 at low doses and enhancing the antiproliferative effects of higher doses by as much as 1000-fold. These data are consistent with the hypothesis that E2 in the ER+ cells blocks the antiproliferative effects of the analogues and suggest the potential usefulness of combined antiestrogen and 1,25(OH)2D3 analogues in ER+ breast tumors, whereas 1,25(OH)2D3 analogues alone might suffice in ER- breast tumors.
Love-Schimenti
C D
CD
Endocrine Research Unit 111N, University of California, San Francisco, Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Gibson
D F
DF
Ratnam
A V
AV
Bikle
D D
DD
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D009363:Neoplasm Proteins; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C087630:1,25-dihydroxy-16-ene-vitamin D3; D004958:Estradiol; C051781:ICI 164384; D002117:Calcitriol; C051883:maxacalcitol; C064183:Ro 23-7553; C078903:seocalcitol