Abstract
Although a large fraction of high-grade serous epithelial ovarian cancers (OCs) expresses Estrogen Receptor alpha (ERα), anti-estrogen-based therapies are still not widely used against these tumors due to a lack of sufficient evidence. The histone methyltransferase Disruptor of telomeric silencing-1-like (DOT1L), which is a modulator of ERα transcriptional activity in breast cancer, controls chromatin functions involved in tumor initiation and progression and has been proposed as a prognostic OC biomarker. As molecular and clinico-pathological data from TCGA suggest a correlation between ERα and DOT1L expression and OC prognosis, the presence and significance of ERα/DOT1L association was investigated in chemotherapy-sensitive and chemotherapy-resistant ER+ OC cells. RNA sequencing before and after inhibition of these factors showed that their activity is implicated in OC cell proliferation and that they functionally cooperate with each other to control the transcription of genes involved in key cancer cell features, such as the cell cycle, epithelial-mesenchymal transition (EMT), drug metabolism, and cell-to-cell signaling, as well as expression of the ERα gene itself. Together with evidence from loss-of-function genetic screens showing that ERα and DOT1L behave as core fitness factors in OC cells, these results suggest that combined inhibition of their activity might be effective against ERα-expressing, chemotherapy-resistant ovarian tumors.
Highlights
Ovarian cancer (OC) represents a heterogeneous tumor, traditionally classified according to histologic and differentiation grade features [1]
Together with evidence from loss-of-function genetic screens showing that ERα and Disruptor of telomeric silencing-1-like (DOT1L) behave as core fitness factors in OC cells, these results suggest that combined inhibition of their activity might be effective against ERα-expressing, chemotherapy-resistant ovarian tumors
ERα protein, resulted in a key gene in both these OC cell lines, since its inactivation caused a loss of fitness, which indicated that this receptor is a favorable therapeutic target in these cells
Summary
Ovarian cancer (OC) represents a heterogeneous tumor, traditionally classified according to histologic and differentiation grade features [1]. Among OCs, high-grade serous ovarian cancer (HGSOC) represents the most aggressive and lethal form of epithelial ovarian cancer and, responding among others to platinum-based therapies, the majority of patients relapse after acquiring resistance to first-line treatment [2]. Estrogen receptors (ERs) are expressed in several OC histotypes, with high expression in serous ones, but endocrine therapy has been used with modest and variable results in the treatment of OC [3] sometimes due to the expression of both ERα and ERβ receptor subtypes, which behave in opposite ways after anti-estrogen administration. ERα has been implicated as a promoter of metastasis in HGSOC through its involvement in lymphovascular space invasion [7]
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