TY - JOUR
T1 - A role for BRCA1 in uterine leiomyosarcoma
AU - Xing, Deyin
AU - Scangas, George
AU - Nitta, Mai
AU - He, Lei
AU - Xu, An
AU - Ioffe, Yevgeniya J.M.
AU - Aspuria, Paul Joseph
AU - Hedvat, Cyrus Y.
AU - Anderson, Matthew L.
AU - Oliva, Esther
AU - Karlan, Beth Y.
AU - Mohapatra, Gayatry
AU - Orsulic, Sandra
PY - 2009/11/1
Y1 - 2009/11/1
N2 - 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 andthat 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 showedthat the BRCA1 protein is absent in 29% of human ULMS andthat 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.
AB - 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 andthat 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 showedthat the BRCA1 protein is absent in 29% of human ULMS andthat 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.
UR - http://www.scopus.com/inward/record.url?scp=70350528669&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70350528669&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-09-2543
DO - 10.1158/0008-5472.CAN-09-2543
M3 - Article
C2 - 19843854
AN - SCOPUS:70350528669
VL - 69
SP - 8231
EP - 8235
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 21
ER -