title: Retinoid-resistant estrogen receptor-negative human breast carcinoma cells transfected with retinoic acid receptor-alpha acquire sensitivity to growth inhibition by retinoids.
abstract: Retinoids mediate their actions via RARs (retinoic acid receptors) and RXRs (retinoid X receptors). Each class of these nuclear retinoid receptors is further subdivided into three species, namely alpha, beta, and gamma. Recent studies demonstrate that estrogen receptor (ER)-positive human breast carcinoma (HBC) cell lines and tumor samples exhibit significantly higher levels of RAR alpha than their ER-negative counterparts. ER-positive HBC cell lines are sensitive to, and ER-negative cell lines are resistant to, growth inhibitory effects of retinoic acid (RA). We previously demonstrated that the expression of functional ERs in an established ER-negative cell line resulted in higher levels of RAR alpha and sensitivity to growth inhibition by RA. To further investigate the major role of RAR alpha in retinoid-mediated inhibition of growth, we transfected RAR alpha cDNA in two RA-resistant ER-negative HBC cell lines. Analyses of different clonal populations of RAR alpha transfectants from each cell line revealed growth inhibition by retinoids. Utilizing RAR- and RXR-class selective retinoids, we further demonstrated that only the RAR alpha-selective retinoids mediated the growth inhibition in these cells, while the RXR-selective retinoids were biologically inert. We thus provide evidence that the molecular mechanisms of retinoid inhibition of HBC proliferation predominantly involve RAR alpha.
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore.
authors.forename: M S
authors.initials: MS
authors.lastname: Sheikh
authors.forename: Z M
authors.initials: ZM
authors.lastname: Shao
authors.forename: X S
authors.initials: XS
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Dawson
authors.forename: A M
authors.initials: AM
authors.lastname: Jetten
authors.forename: S
authors.initials: S
authors.lastname: Wu
authors.forename: B A
authors.initials: BA
authors.lastname: Conley
authors.forename: M
authors.initials: M
authors.lastname: Garcia
authors.forename: H
authors.initials: H
authors.lastname: Rochefort
authors.forename: J A
authors.initials: JA
authors.lastname: Fontana
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008969:Molecular Sequence Data; D011960:Receptors, Estrogen / Q000172:deficiency*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; C000607071:RARA protein, human; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D014212:Tretinoin