Reactive Oxygen Species in the Initiation, Survival and Racial Disparity of Uterine Leiomyoma

Northwestern University At Chicago, Evanston IL

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Abstract

To date, we do not understand why there is such a high prevalence of uterine leiomyoma in premenopausal women nor do we understand the reasons for the racial disparity observed in this disease. Black women tend to develop tumors earlier and are more numerous, larger in size and more symptomatic than other ethnic groups. We have studied the molecular mechanisms involved in leiomyoma tumor growth and survival as it pertains to hormones and signaling pathways and found that reactive oxygen species (ROS) plays a significant role in leiomyoma pathogenesis. Moreover, for the first time, we discovered that ROS levels and effects on DNA are increased in the myometrial and leiomyoma tissues of Black compared to White women. We hypothesize that ROS promotes mutations in the MED12 gene, to promote leiomyoma tumor formation. In addition, ROS promotes growth and survival of the leiomyoma tumors as estrogen and progesterone provide a homeostatic environment to protect the tumors from the toxicity of high ROS levels. We propose mechanistic and molecular analyses to test our hypothesis including mutational analysis upon chronic treatment with ROS, analysis of ER and PR occupancy on chromatin in response to ROS, and we test the BCL2 inhibitors to target cells where ROS promotes senescence when estrogen and progesterone are absent. In all of our studies, we will compare the tissues from Black versus white women which will generate valuable and novel insight into the racial disparity observed in leiomyoma. We will learn about early changes that may lead to leiomyoma development as well as provide biological rationale to treat leiomyoma tumors with the BCL2 inhibitors. Project Summary/Abstract