No REST for fibroids.

G ood news: A long-awaited model for uterine fibroid tumor research is upon us (1). Historically, there has been a paucity of in vivo models for the study of fibroid tumors (i.e., leiomyomas), benign female pelvic organ tumors characterized by clonal proliferation of smooth muscle cells and expression of genes involved in fibrosis and extracellular matrix (ECM) production. This is staggering, considering that prevalence rates of leiomyomata in women at 50 y of age are nearly 70% in white women and more than 80% in black women (2). This level of penetrance contributes to the high number of hysterectomies performed every year in the United States that equates to crippling medical costs reported to be greater than $2 billion annually (3, 4). In PNAS, Varghese et al. (1) find that the loss of the RE1 silencing transcription factor (REST), a transcriptional repressor, in fibroids resulted in the up-regulation of the G protein-coupled receptor GPR10, which, when activated, increased the proliferation of cultured primary human leiomyoma cells (Fig. 1). They describe their development of a transgenic mouse model that exhibits the leiomyoma phenotype upon expression of GPR10 in uterine smooth muscle cells. This journey began by examining a database (Gene Expression Omnibus dataset GSE13319) that allows comparison of normal human myometrial samples vs. patient fibroid (i.e., leiomyoma) samples (5). They identify GPR10, a receptor known to activate PI3K/AKT signaling, as the most highly dysregulated transcript in fibroids. This observation is important because the PI3K/AKT and mammalian target of rapamycin (MTOR) signaling pathway has been previously implicated in the proliferation of leiomyomas or cells derived from leiomyomas (6–8). The finding that GPR10 may be involved in the genesis of fibroids is surprising because GPR10 was identified as a receptor for prolactin-releasing peptide (PrRP) and is highly expressed in the pituitary (9). Coupled with the expression of GPR10 in patient’s leiomyoma samples was an increase in the activation of AKT and MTOR. Patient leiomyoma cells responded to treatment with a PrRP-31 peptide with an increase in PI3K/AKT/ MTOR signaling and proliferation (Fig. 1), a response not evident in benign normal myometrial-derived smooth muscle cells. Despite the intriguing correlation, it is unknown whether endogenous PrRP contributes to the genesis of fibroids in vivo. Other reports link alterations in GRP10 to metabolic disorders (10), suggesting that additional factors may control the activation of GPR10. The study of Varghese et al. (1) raises many questions and offers possibilities for answering others by using the transgenic mouse model it describes. GPR10 overexpression in the mouse results in myometrial hyperplasia with ECM deposition mimicking that observed with uterine fibroids. Unlike the human phenotype, in which multifocal lesions are common, the mouse phenotype appears to encompass the bulk of the myometrial component. There is no doubt this is attributed to the driver system allowing targeted overexpression to uterine smooth muscle cells. Despite the differences, it raises several interesting questions related to the cause of focal genesis of the lesions in the human. Adding the fact that fibroids are considered clonal, how is it that spontaneously yet simultaneously localized leiomyoma arise in or on the uteri? The mouse model developed a pronounced uterine fibroid-like phenotype. Despite the cause and effect of GPR10 overexpression with increased deposition of ECM, the authors appreciate that this is an oversimplification based on receptor expression alone, and is likely only the beginning of an anticipated complex story. Future studies are needed to determine if knockdown or loss of REST in benign myometrial cells is sufficient to influence their proliferation rate or deposition of ECM. REST transcriptionally represses GPR10 in cell lines (11), which begs the question of whether restoration of REST expression in cultured leiomyoma cells is sufficient to reverse the aberrant proliferation rate or increased ECM deposition characteristic of leiomyoma cells. Theoretically, REST can target and suppress more than 2,000 gene promoters, Fig. 1. Loss of REST in patient leiomyoma cells resulted in the expression of the G protein coupled receptor GPR10 and activation of the AKT/MTOR signaling pathway. Transgenic overexpression of GPR10 in mouse myometrial smooth muscle cells resulted in a phenotype characteristic of human fibroid disease.