Abstract
Uterine leiomyoma (LM) is the most common benign gynecological tumor in premenopausal women. Our previous patient-derived xenograft (PDX) studies established that 17ß-estradiol (E2) and progesterone (P4) stimulate the growth of the two most prevalent subtypes, MED12 mutant (MED12-LM) and HMGA2 overexpressing LMs (HMGA2-LM), via proliferation and hypertrophy of smooth muscle tumor cells (SMTCs). In addition, tumor-associated fibroblasts (TAFs) that do not carry MED12 mutations also contribute to the growth of MED12-LM by secreting extracellular matrix (ECM) proteins. In this study, we investigated the growth control of the fumarate hydratase (FH) deficient LM (FH-LM) subtype, utilizing the PDX model. We identified an FH-negative case with conventional leiomyoma histology. The overexpression of aldo-keto reductase family 1 member B10 (AKR1B10) confirmed the FH deficiency. Like MED12-LM, FH-LM comprised two major cell types: 54.4% SMTCs and 43.3% TAFs. Furthermore, the TAFs expressed FH. The FH-LM PDXs grew in response to E2 and P4 via proliferation and hypertrophy of SMTCs, similar to MED12-LM and HMGA2-LM. While E2 alone did not stimulate growth, E2 was essential for sensitizing FH-deficient SMTCs to P4 by upregulating progesterone receptor (PGR). Our current study established that the growth of the three most prevalent LM subtypes, MED12-LM, HMGA2-LM, and FH-LM, depends on E2 and P4. Thus, selective progesterone receptor modulators (SPRMs) should be an effective treatment option for most symptomatic LM patients.
Competing Interest Statement
The authors have declared no competing interest.