Retinoid-resistant estrogen receptor-negative human breast carcinoma cells transfected with retinoic acid receptor-alpha acquire sensitivity to growth inhibition by retinoids.
Retinoid-resistant estrogen receptor-negative human breast carcinoma cells transfected with retinoic acid receptor-alpha acquire sensitivity to growth inhibition by retinoids.
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发表时间：
1994-08
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通讯作者：
M. Sheikh;M. Sheikh;Z. Shao;Xiao Su Li;M. Dawson;A. Jetten;Suhlan Wu;B. Conley;Marcel Garcia;H. Rochefort;J. Fontana
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作者：
M. Sheikh;M. Sheikh;Z. Shao;Xiao Su Li;M. Dawson;A. Jetten;Suhlan Wu;B. Conley;Marcel Garcia;H. Rochefort;J. Fontana
类维生素A通过RAR（视黄酸受体）和RXR（类维生素A X受体）介导其作用。这些核类视色素受体的每一类别进一步细分为三种，即α、β和γ。最近的研究表明，雌激素受体（ER）阳性的人乳腺癌（HBC）细胞系和肿瘤样品显示出显着更高水平的RAR α比ER阴性的同行。ER阳性HBC细胞系对视黄酸（RA）的生长抑制作用敏感，而ER阴性细胞系对视黄酸（RA）的生长抑制作用具有抗性。我们先前证明，在已建立的ER阴性细胞系中表达功能性ER导致更高水平的RAR α和对RA生长抑制的敏感性。为了进一步研究RAR α在类维生素A介导的生长抑制中的主要作用，我们将RAR α cDNA转染到两个RA抗性ER阴性HBC细胞系中。来自每个细胞系的RAR α转染子的不同克隆群体的分析揭示了类维生素A的生长抑制。利用RAR-和RXR-类选择性类维生素A，我们进一步证明，只有RAR α-选择性类维生素A介导这些细胞的生长抑制，而RXR-选择性类维生素A是生物惰性的。因此，我们提供的证据表明，维甲酸抑制HBC增殖的分子机制主要涉及RAR α。
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.