A role for BRCA1 in uterine leiomyosarcoma.
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.
Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Deyin
D
Xing
George
G
Scangas
Mai
M
Nitta
Lei
L
He
Xuan
X
Xu
Yevgeniya J M
YJ
Ioffe
Paul-Joseph
PJ
Aspuria
Cyrus Y
CY
Hedvat
Matthew L
ML
Anderson
Esther
E
Oliva
Beth Y
BY
Karlan
Gayatry
G
Mohapatra
Sandra
S
Orsulic
D000818:Animals; D054304:Anti-Mullerian Hormone / Q000235:genetics; D019313:BRCA1 Protein / Q000502:physiology*; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D007890:Leiomyosarcoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D014594:Uterine Neoplasms / Q000378:metabolism* / Q000473:pathology
D019313:BRCA1 Protein; D016159:Tumor Suppressor Protein p53; D054304:Anti-Mullerian Hormone; C045073:Cre recombinase; D019426:Integrases