Aromatase gene expression in uterine leiomyoma from African-American women is dramatically higher compared with other races

Abstract

OBJECTIVE: We seek to determine the differential expression of aromatase and steroid receptors in uterine leiomyoma from women of various racial backgrounds. African-American women develop leiomyomata at an earlier age with higher incidence. We hypothesize that the race-specific phenotype may be due to differences in expression of aromatase, estrogen receptor-α (ESR1), estrogen receptor-β (ESR2) and/or progesterone receptor (PGR). Estrogen produced locally by aromatase in uterine leiomyoma may be significant, since aromatase inhibitors reduce tumor size and improve associated symptoms. ESR1 and/or ESR2 may mediate estrogen-dependent growth of leiomyoma. PGR may mediate the effects of antiprogestins that treat leiomyomata.DESIGN: Prospective molecular study.MATERIALS AND METHODS: We collected leiomyoma and adjacent normal-appearing myometrium from women of following racial origins: African-American (n=32), Caucasian (n=34) and Japanese (n=36). After extracting RNA, we used quantitative real-time PCR to quantify mRNA levels of aromatase, ESR1, ESR2 and PGR. Four major alternatively used promoters, each of which is regulated by a distinct set of hormones, control aromatase expression in leiomyoma. We used multiplex PCR to measure aromatase mRNA derived from each of following promoters: II, I.3, I.4 and I.7.RESULTS: In each racial group, levels of aromatase, ESR1, ESR2 and PGR mRNA were significantly higher in leiomyoma compared with adjacent myometrium. In particular, aromatase mRNA levels were strikingly higher in leiomyomata from African-American (86-fold), Caucasian (38-fold) and Japanese (33-fold) women. Intriguingly, this fold difference was significantly higher (2.6-fold) in African-American vs. Japanese women (p=0.025). We also found that promoter II was primarily used to regulate aromatase expression in leiomyoma in vivo. We observed a trend towards higher use of promoter II and I.3 and lower use of I.4 in African-American vs. Japanese or Caucasian women. Contrary to aromatase, the fold-increases of ESR1 and PGR mRNA levels were lower in African-American women than those in Japanese women.CONCLUSIONS: Expression of aromatase, the key enzyme that promotes leiomyoma growth, is dramatically higher in vivo in leiomyomata from African-American women. This striking race-specific difference may in part be due to use of alternative promoters and account for the higher incidence and earlier growth of uterine leiomyoma in African-American women. OBJECTIVE: We seek to determine the differential expression of aromatase and steroid receptors in uterine leiomyoma from women of various racial backgrounds. African-American women develop leiomyomata at an earlier age with higher incidence. We hypothesize that the race-specific phenotype may be due to differences in expression of aromatase, estrogen receptor-α (ESR1), estrogen receptor-β (ESR2) and/or progesterone receptor (PGR). Estrogen produced locally by aromatase in uterine leiomyoma may be significant, since aromatase inhibitors reduce tumor size and improve associated symptoms. ESR1 and/or ESR2 may mediate estrogen-dependent growth of leiomyoma. PGR may mediate the effects of antiprogestins that treat leiomyomata. DESIGN: Prospective molecular study. MATERIALS AND METHODS: We collected leiomyoma and adjacent normal-appearing myometrium from women of following racial origins: African-American (n=32), Caucasian (n=34) and Japanese (n=36). After extracting RNA, we used quantitative real-time PCR to quantify mRNA levels of aromatase, ESR1, ESR2 and PGR. Four major alternatively used promoters, each of which is regulated by a distinct set of hormones, control aromatase expression in leiomyoma. We used multiplex PCR to measure aromatase mRNA derived from each of following promoters: II, I.3, I.4 and I.7. RESULTS: In each racial group, levels of aromatase, ESR1, ESR2 and PGR mRNA were significantly higher in leiomyoma compared with adjacent myometrium. In particular, aromatase mRNA levels were strikingly higher in leiomyomata from African-American (86-fold), Caucasian (38-fold) and Japanese (33-fold) women. Intriguingly, this fold difference was significantly higher (2.6-fold) in African-American vs. Japanese women (p=0.025). We also found that promoter II was primarily used to regulate aromatase expression in leiomyoma in vivo. We observed a trend towards higher use of promoter II and I.3 and lower use of I.4 in African-American vs. Japanese or Caucasian women. Contrary to aromatase, the fold-increases of ESR1 and PGR mRNA levels were lower in African-American women than those in Japanese women. CONCLUSIONS: Expression of aromatase, the key enzyme that promotes leiomyoma growth, is dramatically higher in vivo in leiomyomata from African-American women. This striking race-specific difference may in part be due to use of alternative promoters and account for the higher incidence and earlier growth of uterine leiomyoma in African-American women.