This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-09-2543v1 69/21/8231    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Xing, D. Articles by Orsulic, S. PubMed PubMed Citation Articles by Xing, D. Articles by Orsulic, S.

A Role for BRCA1 in Uterine Leiomyosarcoma

¹ Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts; ² Department of Pathology, Massachusetts General Hospital and ³ Department of Pathology, Harvard Medical School, Boston, Massachusetts; ⁴ Women's Cancer Research Institute, Cedars-Sinai Medical Center, Los Angeles, California; ⁵ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; and ⁶ Division of Gynecologic Oncology, Baylor College of Medicine, Houston, Texas

Requests for reprints: Sandra Orsulic, Women's Cancer Research Institute, Cedars-Sinai Medical Center, 8635 West 3rd Street, Suite 290W, Los Angeles, CA 90048. Phone: 310-423-9546; Fax: 310-423-9537; E-mail: orsulics{at}cshs.org.

Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy with a low survival rate. Currently, there is no effective treatment for ULMS. Infrequent occurrences of human ULMS hamper the understanding of the initiation and progression of the disease, thereby limiting the ability to develop efficient therapies. To elucidate the roles of the p53 and BRCA1 tumor suppressor genes in gynecologic malignancies, we generated mice in which p53 and/or BRCA1 can be conditionally deleted using anti-Müllerian hormone type II receptor (Amhr2)–driven Cre recombinase. We showed that conditional deletion of p53 in mice results in the development of uterine tumors that resemble human ULMS and that concurrent deletion of p53 and BRCA1 significantly accelerates the progression of these tumors. This finding led to our hypothesis that BRCA1 may play a role in human ULMS development. Consistent with this hypothesis, we showed that the BRCA1 protein is absent in 29% of human ULMS and that BRCA1 promoter methylation is the likely mechanism of BRCA1 downregulation. These data indicate that the loss of BRCA1 function may be an important step in the progression of ULMS. Our findings provide a rationale for investigating therapies that target BRCA1 deficiency in ULMS. [Cancer Res 2009;69(21):8231–5]

Key Words: BRCA1 • gynecologic malignancy • mouse model • p53 • uterine leiomyoma • uterine leiomyosarcoma • ULMS