title: Mammary carcinoma suppression by cellular retinoic acid binding protein-II.
abstract: Retinoic acid (RA) modulates cell proliferation, differentiation, and apoptosis, and is used in chemotherapy and chemoprevention in several human cancers. RA exerts its pleiotropic activities by activating the nuclear receptors, retinoic acid receptor (RAR), which, in turn, regulate transcription of multiple target genes. In cells, RA also associates with cellular RA-binding proteins [cellular RA binding proteins (CRABPs)-I and -II]. Recent studies revealed that CRABP-II functions by "channeling" RA to RAR, thereby enhancing the transcriptional activity of the receptor. In search for a biologically meaningful role for CRABP-II, we examined its effect on RA-induced growth inhibition in RA-resistant tumors. Stable expression of CRABP-II in mammary carcinoma SC115 cells enabled activation of RAR, considerably sensitized the cells to RA-induced growth inhibition, and dramatically suppressed their tumorigenicity in immunodeficient mice. Similarly, injection of an adenovirus expressing CRABP-II into mammary carcinomas that spontaneously develop in TgN(MMTVneu)202Mul mice resulted in a significant delay in tumor growth and in prolonged survival rates. Remarkably, in both mouse models, administration of exogenous RA had no additional beneficial effect, indicating that endogenous levels of RA are sufficient for maximal tumor suppression on CRABP-II overexpression. The observations reveal that CRABP-II plays a critical role in sensitizing tumors to the growth-suppressive activities of RA in vivo.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Manor
authors.forename: Elena N
authors.initials: EN
authors.lastname: Shmidt
authors.forename: Anuradha
authors.initials: A
authors.lastname: Budhu
authors.forename: Andrea
authors.initials: A
authors.lastname: Flesken-Nikitin
authors.forename: Marsha
authors.initials: M
authors.lastname: Zgola
authors.forename: Rodney
authors.initials: R
authors.lastname: Page
authors.forename: Alexander Yu
authors.initials: AY
authors.lastname: Nikitin
authors.forename: Noa
authors.initials: N
authors.lastname: Noy
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin