Patient-derived xenograft studies of fumarate hydratase (FH) -deficient uterine leiomyoma subtype.

Abstract

Uterine leiomyoma (LM) is the most common benign gynecological tumor in premenopausal women. Our previous patient-derived xenograft (PDX) studies established that 17{beta}-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.