High aromatase expression in uterine leiomyoma tissues of African-American women

Abstract

Context: Symptomatic uterine leiomyoma is associated with irregular uterine bleeding, anemia, and recurrent pregnancy loss. African-American women develop uterine leiomyomas at an earlier age and with higher frequency compared with Caucasian-American women or other races; however, the underlying mechanism for this discrepancy is unknown.

Objective: Our objective was to determine whether gene targets of emerging leiomyoma therapeutics such as aromatase inhibitors and antiprogestins, which reduce tumor size and symptoms, are differentially expressed in tissues of African-American (n = 31), Caucasian-American (n = 34), and Japanese women (n = 36).

Results: We found strikingly higher aromatase mRNA levels in leiomyoma compared with adjacent myometrium in African-American (83 fold), Caucasian-American (38 fold), and Japanese women (33 fold). Among the four major promoters that regulate aromatase expression in leiomyoma, the proximal promoter II accounted for higher aromatase mRNA levels in tissues from African-American women. Estrogen receptor subtype alpha mRNA levels were significantly, and 1.8- to 2.6-fold, higher in leiomyoma compared with adjacent myometrium in all groups, whereas leiomyoma estrogen receptor subtype beta mRNA levels were significantly elevated only in Japanese women. Leiomyoma progesterone receptor mRNA levels were significantly higher in Japanese women compared with African-American or Caucasian-American women.

Conclusions: Leiomyoma tissues from African-American women contained the highest level of aromatase expression, which may result in elevated tissue concentrations of estrogen, and account for the higher prevalence and earlier incidence. Analysis of leiomyoma tissue for biomarkers may predict the response to hormonal treatments such as aromatase inhibitors.

Figure 1

Expression of aromatase mRNA and promoter (Prom) usage in uterine leiomyomas of African-American, Caucasian-American, and Japanese women. A, Cycle threshold (C_t) values for aromatase mRNA are shown. Aromatase mRNA levels (not adjusted to GAPDH mRNA) in leiomyoma and adjacent-matched myometrial tissues were measured by quantitative real-time RT-PCR, and the required PCR cycles (C_t values) for aromatase mRNA are shown. B, Aromatase mRNA levels in leiomyoma, which were normalized to GAPDH mRNA levels, were described as fold differences compared with matched myometrium. C, Leiomyoma aromatase mRNA levels assorted with menstrual cycle are shown. They were subdivided as proliferative phase and secretory phase. D, Exon-specific multiplex PCR, as described in Subjects and Methods, was used to quantify aromatase mRNA species specific for each of the promoters II, I.3, I.4, or I.7. Each promoter-specific aromatase mRNA level was represented as a percentage of the sum of all four promoter-specific mRNA levels. *, P < 0.05 and **, P < 0.01 by the Wilcoxon signed-rank test for leiomyoma vs. myometrium, and by ANOVA with pairwise t tests for African-American subjects vs. Japanese subjects, Caucasian-American subjects vs. Japanese subjects, or African-American subjects vs. Caucasian-American subjects.

Figure 2

Expression of estrogen receptor and PR mRNA in uterine leiomyomas of African-American, Caucasian-American, and Japanese women. ERα (A), ERβ (B), or PR (C) mRNA levels in uterine leiomyoma and matched myometrium were measured by quantitative real-time RT-PCR and were normalized to GAPDH mRNA levels. All values in leiomyoma were described as fold differences compared with those measured in matched myometrium. *, P < 0.05 and **, P < 0.01 by Wilcoxon signed-rank test for leiomyoma vs. myometrium, and by ANOVA with pairwise t tests for African-American subjects vs. Japanese subjects, Caucasian-American subjects vs. Japanese subjects, or African-American subjects vs. Caucasian-American subjects.