Uterine leiomyomas express a molecular pattern that lowers retinoic acid exposure

Objective: To analyze expression of the retinoic acid signaling pathway genes that are involved in retinol metabolism, transport, transcriptional activation, and transcriptional products in spontaneous human leiomyomas. Design: Laboratory study of human leiomyoma and patient-matched myometrial tissue. Patient(s): Eight women undergoing hysterectomy for symptomatic leiomyomas. Intervention(s): Confirmation of an altered retinoic acid pathway analyzed by microarray, real time reverse transcription-polymerase chain reaction, Western blot, immunohistochemistry, and high-performance liquid chromatography (HPLC). Main Outcome Measure(s): Gene and protein expression. Result(s): Regardless of patient demographics and leiomyoma location and size, we found decreased expression of the major genes involved in retinoic acid pathway including alcohol dehydrogenase-1 (-3.97- ± 0.03-fold), aldehyde dehydrogenase-1 (-3.1- ± 0.07-fold), cellular retinol binding protein-1 (-2.62- ± 0.04-fold), and cellular retinoic acid binding protein-1 (-2.42- ± 0.20-fold). Cytochrome P450 (CYP 26A1), which is responsible for retinoic acid metabolism, was highly up-regulated in leiomyomas (+5.4- ± 0.53-fold). Nuclear receptors demonstrated a complex pattern of under-expression (RARα, RARβ, RXRα, RXRγ) and over-expression (RARγ, RXRβ) at both the mRNA and protein level. Differences in protein amounts were confirmed by Western blot. Finally, a reduced amount of cellular ATRA and 9-cis retinoic acid was confirmed by HPLC in leiomyomas compared with myometrial tissues. Conclusion(s): Molecular alterations in the retinoic acid pathway of leiomyomata result in a decrease in retinoic acid exposure.