Signal transduction pathway activity in high-grade serous carcinoma, its precursors and Fallopian tube epithelium

Phyllis Van Der Ploeg,Aniek Uittenboogaard,Steven L Bosch,Paul J Van Diest,Yvonne J.W Wesseling-Rozendaal,Anja Van De Stolpe,Sandrina Lambrechts,Ruud L.M Bekkers,Jurgen M.J Piek

doi:10.1016/j.ygyno.2022.01.027

Abstract

ObjectiveTo determine the activity of key signal transduction pathways in serous tubal intraepithelial carcinoma (STIC) and concurrent high-grade serous carcinoma (HGSC) and compare this to pathway activity in normal Fallopian tube epithelium (FTE). MethodsWe assessed mRNA expression levels of pathway-specific target genes with RT-qPCR in STIC and concurrent HGSC (n = 8) and normal FTE (n = 8). Subsequently, signal transduction pathway assays were used to assess functional activity of the androgen (AR) and estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathways. ResultsThere were no statistically significant differences in pathway activity between STIC and HGSC, but STIC and HGSC demonstrated significantly lower ER and higher PI3K and HH pathway activity in comparison to normal FTE, suggesting these pathways as putative early drivers. In addition, we determined FOXO3a protein expression by immunohistochemistry and found loss of FOXO3a protein expression in STIC and HGSC compared to normal FTE. This observation confirmed that activation of PI3K signaling by loss of FOXO is an early hallmark of serous carcinogenesis. Furthermore, HGSC demonstrated significant loss of AR and Wnt pathway activity in relation to FTE, suggesting these pathways contribute to disease progression. ConclusionOur observations, together with the previously described associations between p53 signaling and both PI3K and HH pathway activity, provide evidence that increased PI3K and HH pathway activity and loss of ER pathway activity may be underlying events contributing to neoplastic transformation of FTE into STIC.

Highlights

Nonuterine high-grade serous carcinoma (HGSC) refers to ovarian, Fallopian tube and primary peritoneal cancers [1]
Eight normal Fallopian tube epithelium (FTE), eight serous tubal intraepithelial carcinoma (STIC) samples and seven concurrent HGSC samples were available for the analysis of signal transduction pathways (STPs) activity
We assessed the activity of key STPs in normal FTE, STIC and HGSC samples in order to identify early aberrations in STP activity that may drive the development of FTE precursors and progression into HGSC

Summary

Introduction

Nonuterine high-grade serous carcinoma (HGSC) refers to ovarian, Fallopian tube and primary peritoneal cancers [1]. The ovarian surface epithelium was proposed as the cell of origin of HGSC [4] Two decades ago, another hypothesis evolved as preneoplastic changes were observed in the epithelium of the fimbriae of prophylactically removed Fallopian tubes of women with a hereditary high risk to develop HGSC, but not in the ovarian surface epithelium [5,6]. Another hypothesis evolved as preneoplastic changes were observed in the epithelium of the fimbriae of prophylactically removed Fallopian tubes of women with a hereditary high risk to develop HGSC, but not in the ovarian surface epithelium [5,6] These non-invasive dysplastic precursor lesions, later named serous tubal intraepithelial carcinoma (STIC), were observed in Fallopian tubes of women with non-hereditary HGSC [7].

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