Uterine fibroids (also known as leiomyomas or myomas) are common clonal neoplasms of the uterus. Fibroids have both smooth muscle and fibroblast components, in addition to a substantial amount of fibrous extracellular matrix, which all contribute to the pathogenetic process. Fibroids are extremely heterogeneous in their pathophysiology, size, location and clinical symptomatology. They are also a part of a range of disease in which some variants have facets of malignant behaviour but overall are benign. Risk for fibroids is associated with race; black women have a higher risk of developing fibroids earlier in life than their white counterparts and also develop more-severe forms of the disease. Clinically, fibroids account for one-third to half of all hysterectomies and are associated with substantial morbidity and health care costs for women of reproductive age. Indeed, current treatments are primarily surgical and interventional; approximately three-quarters of all fibroid treatments are hysterectomies. However, clinical innovations are emerging in the use of progesterone receptor modulators as a medical therapy. New information is rapidly accumulating about the genetic subgroups that lead to fibroid formation, which might aid further understanding of the clinical heterogeneity of this disease and lead to individualized treatments. This information is a crucial development given the current lack of high-quality evidence on which to base therapeutic decisions.

This article will discuss some recent insights based on our microarray studies that have emphasized the role the extracellular matrix, transforming growth factor beta, and collagen structure in fibroid formation. These studies led to appreciation of molecular similarities between fibroids and keloids. Collectively, these observations suggest a model of fibroid development based on an abnormal response to tissue repair, resulting in disordered healing and formation of an altered extracellular matrix.

Uterine leiomyomas are prevalent estrogen-responsive clonal tumors, but the specific genetic alterations that contribute to their development have not been elucidated. To identify genes involved in the formation of leiomyomas, we used global expression profiling to compare clonal tumors with normal myometrium. Contrary to expectation, genes involved in estrogen action were not differentially expressed between leiomyoma and normal myometrium. Genes encoding extracellular-matrix proteins were prominently featured, suggesting their involvement in formation of a myofibroblast phenotype. Analysis of the extracellular matrix in the leiomyomas revealed a disordered collagen fibril orientation. Expression of the collagen-binding protein dermatopontin was found to be consistently decreased in leiomyoma by both reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time RT-PCR (mean underexpression = 9.41-fold) regardless of leiomyoma size, leiomyoma location, patient race, and patient age. This expression pattern was observed in 11 subjects and a total of 23 leiomyoma:myometrium pairs. Decreased expression of dermatopontin was also associated with keloid formation, a fibrotic disease that shares epidemiologic similarities with leiomyoma. Immunohistochemical studies of leiomyomas and keloids demonstrated reduced levels of dermatopontin in both tissues. In addition, ultrastructural analysis revealed that the orientation of the collagen fibrils in the keloid tissues strongly resembled that in the leiomyomas. Reduction in dermatopontin was associated with an increase in transforming growth factor-beta3 (TGFB3) mRNA levels in leiomyomas, whereas other genes involved in dermatopontin signaling were not differentially expressed. These findings suggest that leiomyoma development involves a myofibroblast cell phenotype characterized by dysregulation of genes encoding extracellular-matrix proteins. In particular, decreased expression of dermatopontin represents a molecular link between the leiomyoma and keloid phenotypes.

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