Compensatory alterations in energy homeostasis characterized in uterine tumors from hereditary leiomyomatosis and renal cell cancer.

ABSTRACT

OBJECTIVE: To determine the molecular alterations that maintain energy homeostasis in hereditary leiomyomatosis and renal cell cancer (HLRCC) uterine tumors with disrupted fumarate hydratase, compared with nonsyndromic uterine tumors. DESIGN: Laboratory study. SETTING: Tertiary academic university hospital. PATIENT(S) Eleven nonsyndromic leiomyoma-myometrium pairs and three HLRCC leiomyoma-myometrium pairs were obtained from patients who were recruited at national and military research centers in the United States. INTERVENTION(S) Molecular analysis. MAIN OUTCOME MEASURE(S) Hereditary leiomyomatosis and renal cell cancer and nonsyndromic leiomyomas were compared with patient-matched myometrium for relative glycolysis and Krebs cycle gene expression. RESULT(S) By microarray analysis, we confirmed that fumarate hydratase messenger RNA (mRNA) was underexpressed in HLRCC fibroids, compared with matched myometrium. Consistent with the possibility that alterations in fumarate hydratase represented a change to a more anaerobic state, we found that HLRCC fibroids overexpressed genes such as phosphofructokinase, aldolase, phosphoglycerate kinase, enolase, and pyruvate kinase. Expression of these genes was not altered in nonsyndromic leiomyomas. Furthermore, there were no overt changes in expression of Krebs cycle enzyme gene expression, with the exception of fumarate hydratase. CONCLUSION(S) Our findings demonstrate that alterations in fumarate hydratase are compensated for by increases in glycolysis enzyme expression in HLRCC.