Vitamin D receptor-dependent inhibition of mammary tumor growth by EB1089 and ultraviolet radiation in vivo.
1,25-Dihydroxyvitamin D(3) (1,25D), the biologically active form of vitamin D(3), exerts antiproliferative and proapoptotic effects in multiple transformed cell types, and thus, the vitamin D signaling pathway represents a potential anticancer target. Although chronic treatment with 1,25D induces hypercalcemia, synthetic vitamin D analogs have been developed that inhibit tumor growth in vivo with minimal elevation of serum calcium. Furthermore, vitamin D is synthesized in skin exposed to UV light, and this route of vitamin D elevation is not associated with hypercalcemia. In this study, we examined whether enhancement of vitamin D status via exogenous (EB1089, a 1,25D analog) or endogenous (UV exposure) approaches could exert antitumor effects without hypercalcemia. We used mammary xenografts with differential vitamin D receptor (VDR) expression to examine whether the antitumor effects of either therapy are receptor mediated. We present evidence that both EB1089 and UV exposure inhibit tumor growth via induction of growth arrest and apoptosis. These antitumor effects were observed only in xenografts containing VDR-positive tumor cells; heterogeneous tumors containing VDR-negative tumor cells and VDR-positive stromal and endothelial cells were unresponsive to both therapies. No evidence for antiangiogenic effects of EB1089 were detected in this model system. Neither EB1089 nor UV was associated with overt toxicity, but keratinocyte proliferation was increased in UV-exposed skin. These data provide proof of principle that UV exposure modulates tumor growth via elevation of vitamin D signaling and that therapeutic approaches designed to target the vitamin D pathway will be effective only if tumor cells express functional VDR.
Valrance
Meggan E
ME
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
Brunet
Andrea H
AH
Welsh
JoEllen
J
D000818:Animals; D017209:Apoptosis; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D004817:Epidermis / Q000473:pathology / Q000528:radiation effects; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D014183:Transplantation, Heterologous; D014466:Ultraviolet Rays
D018167:Receptors, Calcitriol; D002117:Calcitriol; C078903:seocalcitol