Retinoic Acid Receptor and Retinoid × Receptor in Ductal Carcinoma in situ and Intraductal Proliferative Lesions of the Human Breast

Abstract

Retinoic acid (RAR) and retinoid X receptors (RXR) are essential in the transcriptional actions of retinoids. To date, RAR and RXR have not been examined in precancerous lesions and/or ductal carcinoma in situ (DCIS) in human breast. Therefore, we examined RAR and RXR subtypes in DCIS (58 cases), atypical ductal hyperplasia (ADH) (32 cases), and proliferative disease without atypia (PDWA) (32 cases) to study the status of these RARs and RXRs. Immunoreactivities for RAR α α α α, RXR α α α α, RXR β β β β, and RXR γ γ γ γ were all detected in the nuclei of normal ductal epithelia. Immunoreactivity for RAR Key words: RAR -RXR -DCIS -Human breast -Proliferative diseaseVitamin A-derived retinoids are well known to regulate cell proliferation and differentiation in a wide range of tissues and cell types.1, 2) Retinoids can also inhibit the proliferation of a large variety of normal and neoplastic cell types in vitro, [3][4][5][6][7] and recently they have been used successfully in the treatment and prevention of a number of human malignant neoplasms, such as acute promyelocytic leukemia.8, 9) These effects are mainly mediated by two classses of nuclear retinoid receptors, which belong to the steroid/thyroid hormone receptor superfamily, retinoic acid receptors (RARs) [10][11][12][13][14] and retinoid X receptors (RXRs). [15][16][17] Retinoid receptors are known to function as heterodimers of RAR and RXR, or as RXR homodimers, and to activate transcription in a ligand-dependent manner by binding to retinoic acid-responsive elements (RAREs) located in the promoter region of various target genes. 18)Both RARs and RXRs are composed of three subtypes: α, β, and γ. The expression patterns of these retinoid receptor subtypes have been considered to regulate the expression of distinct target genes and the actions of retinoids. 19) Despite the established roles of retinoids in the inhibition of growth in human breast cancer cell lines, [20][21][22] and the potential roles of retinoids in chemoprevention or therapy of breast cancer, 6,23) relatively limited information is available on the expression of retinoid receptors and/or the actual biological effects of retinoids in human breast carcinoma tissues. In advanced human breast carcinomas, an increased expression of RAR α has been reported, 24) and recently, decreased expression of RAR β mRNA has been reported. 25) Chemoprevention utilizing retinoids appears to be more effective in the early phase of cancer, or in the premalignant phase than in the advanced phase of cancer. 3,26,27) However, expression of retinoid receptors has been little studied in the early phase of breast cancer, i.e., ductal carcinoma in situ (DCIS) 28) or other intraductal proliferative lesions such as atypical ductal hyperplasia (ADH). The anti-proliferative effects of retinoids have been recognized mainly in hormone-dependent or estrogen receptor (ER)-positive breast carcinoma, but hardly in hormone-independent or ER-negative breast carcinoma. [29][30][31] Additionally, it is known that there are more ...

Breast cancer proteomics by laser capture microdissection, sample pooling, 54‐cm IPG IEF, and differential iodine radioisotope detection

“…They bind to homo-or heterodimers of the retinoic acid (RAR) or retinoid X (RXR) receptor families, as well as other proteins, and the concentrations of these components influence the retinoid response [34,35]. For instance, higher levels of the RARalpha are associated with greater proliferation rates of ER 1 ductal carcinoma in situ breast cancer [36]. Retinoid receptors influence a diverse range of proteins involved in signal transduction and cell cycle control, and make direct protein interaction with various kinases and transcription factors [34].…”

Controversies of aromatase localization in human breast cancer—Stromal versus parenchymal cells

“…Mu et al [36] reported that the combined treatment of two types of retinoids, TTNPB for RAR and LG100268 for RXR synergistically stimulate aromatase enzymatic activity in MCF-7. These nuclear receptors such as ERR␣, RAR, and RXR were all detected in parenchymal carcinoma cells but not in stromal nor in normal epithelial cells of breast carcinoma tissues [37][38][39]. In RT-PCR analysis of aromatase (Fig.…”

Expression of the Steroid and Xenobiotic Receptor and Its Possible Target Gene, Organic Anion Transporting Polypeptide-A, in Human Breast Carcinoma

“…However, we did not detect either SXR mRNA or protein in normal human breast tissues. We reported previously that the obligate SXR heterodimeric partner, retinoid X receptor, was only very weakly expressed in normal breast cells (36,37). SXR was also detected in hormone-dependent endometrial carcinoma cell but not in normal endometrium (13).…”