FOXO3a loss is a frequent early event in high-grade pelvic serous carcinogenesis

Abstract

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 (HGSOCs). 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.

Role of microRNAs in cancers of the female reproductive tract: insights from recent clinical and experimental discovery studies

“…Serous tubal intraepithelial carcinoma (STIC) lesions in fimbria may be the precursor lesions for high-grade serous EOC. Additionally studies support the role of overexpression of miR-182a in suppression of FOXO3A in fallopian tube cells leading to high-grade serous EOC [79]. Forced overexpression of miR-182 in vitro lead to increased cellular transformation, likely through dysregulation of DNA repair pathways involving BRCA1, MTSS1 and HMGA2 [78].…”

Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis

“…Loss of FOXO3a has been observed in various cancers [14,51], and its cellular localization and phosphorylation status are considered to be prognostic factors for acute myeloid leukemia [52], breast [15,53], prostate [54], and ovarian cancer [55]. FOXO3a is primarily regulated by posttranslational mechanisms.…”

Human endometrial mesenchymal stem cells exhibit intrinsic anti-tumor properties on human epithelial ovarian cancer cells

“…Levanon et al . illustrated that FoxO3a loss is a frequent early event in high grade serous ovarian carcinoma22. FoxO3a also shows prognostic value in ovarian cancer patients, whose low expression level is associated with poor prognosis23.…”