Retinoid-resistant estrogen receptor-negative human breast carcinoma cells transfected with retinoic acid receptor-alpha acquire sensitivity to growth inhibition by retinoids

• Published in: The Journal of biological chemistry Vol. 269; no. 34; pp. 21440 - 21447
• Main Authors: Sheikh, M S, Shao, Z M, Li, X S, Dawson, M, Jetten, A M, Wu, S, Conley, B A, Garcia, M, Rochefort, H, Fontana, J A
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 26.08.1994
• Subjects: Base Sequence; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Carcinoma - genetics; Carcinoma - metabolism; Cell Division - drug effects; DNA, Complementary - genetics; Female; Genetic Vectors; Humans; Molecular Sequence Data; Receptors, Estrogen - deficiency; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; Retinoic Acid Receptor alpha; Retinoids - pharmacology; Signal Transduction; Transfection; Tretinoin - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(17)31823-9

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.