Crabtree Judy S, Jelinsky Scott A, Harris Heather A, Choe Sung E, Cotreau Monette M, Kimberland Michelle L, Wilson Ewa, Saraf Kathryn A, Liu Wei, McCampbell Adrienne S, Dave Bhuvanesh, Broaddus Russell R, Brown Eugene L, Kao Wenling, Skotnicki Jerauld S, Abou-Gharbia Magid, Winneker Richard C, Walker Cheryl L
Endocrinology & Reproductive Disorders Division, Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, Pennsylvania, USA.
Cancer Res. 2009 Aug 1;69(15):6171-8. doi: 10.1158/0008-5472.CAN-08-4471. Epub 2009 Jul 21.
Uterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% of reproductive-age women. Despite being the primary cause of hysterectomy in the United States, accounting for up to 200,000 procedures annually, the etiology of leiomyoma remains largely unknown. As a basis for understanding leiomyoma pathogenesis and identifying targets for pharmacotherapy, we conducted transcriptional profiling of leiomyoma and unaffected myometrium from humans and Eker rats, the best characterized preclinical model of leiomyomata. A global comparison of mRNA from leiomyoma versus myometrium in human and rat identified a highly significant overlap of dysregulated gene expression in leiomyomata. An unbiased pathway analysis using a method of gene-set enrichment based on the sigPathway algorithm detected the mammalian target of rapamycin (mTOR) pathway as one of the most highly up-regulated pathways in both human and rat tumors. To validate this pathway as a therapeutic target for uterine leiomyomata, preclinical studies were conducted in Eker rats. These rats develop uterine leiomyomata as a consequence of loss of Tsc2 function and up-regulation of mTOR signaling. Inhibition of mTOR in female Eker rats with the rapamycin analogue WAY-129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly decreased tumor incidence, multiplicity, and size. These results identify dysregulated mTOR signaling as a component of leiomyoma etiology across species and directly show the dependence of uterine leiomyomata with activated mTOR on this signaling pathway for growth.
子宫平滑肌瘤，即纤维瘤，是子宫肌层的良性肿瘤，影响着高达30%的育龄女性。尽管它是美国子宫切除术的主要原因，每年多达20万例手术，但平滑肌瘤的病因在很大程度上仍然未知。作为理解平滑肌瘤发病机制和确定药物治疗靶点的基础，我们对人类和Eker大鼠（平滑肌瘤特征最明确的临床前模型）的平滑肌瘤和未受影响的子宫肌层进行了转录谱分析。对人类和大鼠平滑肌瘤与子宫肌层的mRNA进行全面比较，发现平滑肌瘤中基因表达失调存在高度显著的重叠。使用基于sigPathway算法的基因集富集方法进行无偏通路分析，检测到雷帕霉素哺乳动物靶标（mTOR）通路是人类和大鼠肿瘤中上调程度最高的通路之一。为了验证该通路作为子宫平滑肌瘤治疗靶点的有效性，我们在Eker大鼠中进行了临床前研究。这些大鼠由于Tsc2功能丧失和mTOR信号上调而发生子宫平滑肌瘤。用雷帕霉素类似物WAY-129327对雌性Eker大鼠的mTOR进行抑制2周，可降低肿瘤中的mTOR信号和细胞增殖，治疗4个月可显著降低肿瘤发生率、多发性和大小。这些结果表明，mTOR信号失调是跨物种平滑肌瘤病因的一个组成部分，并直接表明激活mTOR的子宫平滑肌瘤的生长依赖于该信号通路。
