FOXO3a loss is a frequent early event in high-grade pelvic serous carcinogenesis.
Serous ovarian carcinoma is the most lethal gynecological malignancy in Western countries. The molecular events that underlie the development of the disease have been elusive for many years. The recent identification of the fallopian tube secretory epithelial cells (FTSECs) as the cell-of-origin for most cases of this disease has led to studies aimed at elucidating new candidate therapeutic pathways through profiling of normal FTSECs and serous carcinomas. Here we describe the results of transcriptional profiles that identify the loss of the tumor suppressive transcription factor FOXO3a in a vast majority of high-grade serous ovarian carcinomas. We show that FOXO3a loss is a hallmark of the earliest stages of serous carcinogenesis and occurs both at the DNA, RNA and protein levels. We describe several mechanisms responsible for FOXO3a inactivity, including chromosomal deletion (chromosome 6q21), upregulation of miRNA-182 and destabilization by activated PI3K and MEK. The identification of pathways involved in the pathogenesis of ovarian cancer can advance the management of this disease from being dependant on surgery and cytotoxic chemotherapy alone to the era of targeted therapy. Our data strongly suggest FOXO3a as a possible target for clinical intervention.
1] The Dr Pinchas Borenstein Talpiot Medical Leadership Program 2012, Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel [2] Department of Medical Oncology; Dana-Farber Cancer Institute, Boston, MA, USA.
K
K
Levanon
Sheba Cancer Research Center; Chaim Sheba Medical Center, Ramat Gan, Israel.
S
S
Sapoznik
Sheba Cancer Research Center; Chaim Sheba Medical Center, Ramat Gan, Israel.
K
K
Bahar-Shany
1] Sheba Cancer Research Center; Chaim Sheba Medical Center, Ramat Gan, Israel [2] Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
H
H
Brand
Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel.
R
R
Shapira-Frommer
Department of Gynecologic Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel.
J
J
Korach
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
M S
MS
Hirsch
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
M H
MH
Roh
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
A
A
Miron
1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
J F
JF
Liu
Center of Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
N
N
Vena
1] Department of Gynecologic Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel [2] Harvard Medical School, Boston, MA, USA [3] Center of Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
A H
AH
Ligon
Center of Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
S
S
Fotheringham
Center of Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
D
D
Bailey
Center of Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
R J
RJ
Flavin
Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
M J
MJ
Birrer
1] Department of Medical Oncology; Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA [3] Harvard Medical School, Boston, MA, USA.
R I
0000000269126977
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Drapkin
D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002896:Chromosomes, Human, Pair 6; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism / Q000473:pathology*; D005187:Fallopian Tubes / Q000378:metabolism / Q000473:pathology; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; C538984:Mirn182 microRNA, human