Expression of p53 and p21 WAF-1 , apoptosis, and proliferation of smooth muscle cells in normal myometrium during the menstrual cycle: implication of DNA damage and repair for leiomyoma development

Uterine leiomyoma is the most common tumor in the female genital tract, although its pathogenesis remains unclear. Molecular analyses have demonstrated that each leiomyoma nodule is monoclonal and harbors various DNA abnormalities, suggesting that DNA damage in normal smooth muscle cells plays an important role in the pathogenesis of leiomyoma. The aim of this study is to evaluate precisely when and where DNA damage occurs in the myometrium. The localization of damaged, apoptotic, and proliferating cells was evaluated by immunohistochemical staining of p53, p21WAF-1, TUNEL, and the cell proliferation marker, Ki-67, in normal myometrium during the menstrual cycle. p53-positive cells and p21WAF-1-positive cells were observed during the follicular phase, mostly in the submucosal layer of the myometrium. TUNEL-positive cells were sporadically identified in this layer during either the menstrual or follicular phase. In contrast, the number of Ki-67-positive cells was higher in the luteal phase. These results suggest that DNA damage, repair, and apoptosis occur cyclically in normal myometrium during the follicular phase. In addition, smooth muscle cells proliferate in the luteal phase, which may be a vulnerable period for DNA damage. Thus, these cyclic events during the menstrual cycle may contribute to a high incidence of leiomyoma development.