Efficacy of Vitamin D compounds to modulate estrogen receptor negative breast cancer growth and invasion.
In estrogen receptor (ER) positive breast cancer cells such as MCF-7 cells, the anti-tumor effects of 1,25(OH)(2)D(3) (1,25D(3)) may be secondary to disruption of estrogen mediated survival signals. If so, then sensitivity to 1,25D(3) mediated growth arrest could be reduced in estrogen independent breast cancer cells. The aim of these studies was to determine the effects of 1,25D(3) and EB1089 on the ER negative, invasive human breast cancer cell line SUM-159PT. 1,25D(3) and EB1089 reduced SUM-159PT cell growth subsequent to elevation of p27 and p21 levels. 1,25D(3) mediated apoptosis of SUM-159PT cells was associated with an enrichment of membrane bound bax, a redistribution of cytochome c from the mitochondria to the cytosol and PARP cleavage. 1,25D(3) and EB1089 also inhibited SUM-159PT cell invasion through an 8 microM Matrigel membrane. In pre-clinical studies, EB1089 dramatically reduced the growth of SUM-159PT xenografts in nude mice. The decreased size of tumors from EB1089 treated mice was associated with decreased proliferation and increased DNA fragmentation. Our data support the concept that Vitamin D(3) compounds trigger apoptosis by mechanisms independent of estrogen signaling. These studies indicate that Vitamin D(3) based therapeutics may be beneficial, alone or in conjunction with other agents, for the treatment of estrogen independent breast cancer.
Flanagan
Louise
L
Department of Biological Sciences, University of Notre Dame, 126 Galvin Life Sciences Building, IN 46556, USA.
Packman
Kathryn
K
Juba
Brian
B
O'Neill
Sharon
S
Tenniswood
Martin
M
Welsh
JoEllen
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001672:Biocompatible Materials / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division; D002762:Cholecalciferol / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004591:Electrophoresis, Polyacrylamide Gel; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D011509:Proteoglycans / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D013347:Subcellular Fractions; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000378:metabolism* / Q000494:pharmacology
D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D004338:Drug Combinations; D047628:Estrogen Receptor alpha; D004967:Estrogens; D007797:Laminin; D008024:Ligands; D011509:Proteoglycans; D018167:Receptors, Calcitriol; D011960:Receptors, Estrogen; C059485:matrigel; D014807:Vitamin D; D002762:Cholecalciferol; D003094:Collagen; D011065:Poly(ADP-ribose) Polymerases; D002117:Calcitriol; C078903:seocalcitol