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 alpha, RXR alpha, RXR beta, and RXR gamma were all detected in the nuclei of normal ductal epithelia. Immunoreactivity for RAR beta was detected exclusively in the nuclei of myoepithelial cells, but not in normal ductal epithelia. Immunoreactivity for RAR gamma was not detected in any of the breast tissues examined except for a few cases of PDWA and ADH, and 11 cases of DCIS. The RXR alpha labeling index (LI) was significantly higher in both DCIS (mean 77.9) and ADH (mean 77.7) than in PDWA (mean 62.8) (P < 0.001). RXR beta LI was significantly lower in DCIS (mean 81.5) than in both ADH (mean 91.1) and PDWA (mean 91.9) (P = 0.0001). Immunoreactivity for RAR alpha, RXR alpha, RXR beta and RXR gamma was widely distributed compared to that of RAR beta and RAR gamma in DCIS, ADH and PDWA. RAR alpha LI was significantly correlated with Ki67 LI in DCIS (P = 0.0040), especially in estrogen receptor (ER)-positive DCIS. Our results suggest that RXRs are much more widely distributed than RARs in intraductal proliferative lesions of tne human breast, but ER-positive DCIS cases with high cell proliferative activity are associated with RAR alpha, suggesting the possible involvement of retinoids through RAR alpha in tumor cell proliferation in DCIS.