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.


METHODS
Laboratory study of human leiomyoma and patient-matched myometrial tissue.


METHODS
Eight women undergoing hysterectomy for symptomatic leiomyomas.


METHODS
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).


METHODS
Gene and protein expression.


RESULTS
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 (RARalpha, RARbeta, RXRalpha, RXRgamma) and over-expression (RARgamma, RXRbeta) 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.


CONCLUSIONS
Molecular alterations in the retinoic acid pathway of leiomyomata result in a decrease in retinoic acid exposure.
Catherino
William H
WH
Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4712, USA. catheriw@mail.nih.gov
Malik
Minnie
M
D000328:Adult; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007044:Hysterectomy; D007150:Immunohistochemistry; D007889:Leiomyoma / Q000235:genetics*; D008597:Menstrual Cycle; D008875:Middle Aged; D009215:Myometrium / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics / Q000302:isolation & purification; D020411:Oligonucleotide Array Sequence Analysis; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000378:metabolism*; D014594:Uterine Neoplasms / Q000235:genetics* / Q000601:surgery
D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D014212:Tretinoin