# Rethinking estrogen receptor β in EAOC: a synergistic modulator in a genomically informed landscape

## TL;DR

This paper re-evaluates the role of estrogen receptor β in endometriosis-associated ovarian cancer, highlighting its modulatory function in cancer progression and signaling pathways.

## Contribution

The paper repositions ERβ as a context-dependent modulator rather than a primary driver in EAOC, emphasizing its interaction with genomic alterations.

## Key findings

- ERβ potentiates pro-survival signaling like the PI3K/AKT pathway in genomically altered EAOC cells.
- The ERβ–BDNF/TrkB signaling axis contributes to apoptosis resistance and metastatic programming.
- Targeting ERβ requires precision medicine strategies tailored to tumor molecular subtypes.

## Abstract

Endometriosis-associated ovarian cancer (EAOC), encompassing subtypes like ovarian clear cell (OCCC) and endometrioid (OEC) carcinoma, represents a distinct Type I malignancy arising from endometriotic lesions. These tumors are characterized by a specific molecular landscape, including high-frequency driver mutations in genes such as ARID1A, PIK3CA, and PTEN. Within this setting, the role of estrogen receptor β (ERβ), whose expression is progressively upregulated during malignant transformation, requires a nuanced re-evaluation. This review repositions ERβ not as a primary oncogenic driver, but as a critical, spatiotemporal modulator. Its principal function appears to be potentiating pro-survival signaling, such as the PI3K/AKT pathway, within a cellular environment already primed by constitutive genetic alterations. Furthermore, ERβ appears to couple apoptosis resistance with microenvironmental remodeling and metastatic programming. We further dissect the role of the downstream ERβ–brain-derived neurotrophic factor (BDNF)/Tropomyosin receptor kinase B (TrkB) signaling axis, proposing it as a key cooperative network that provides parallel and compensatory survival signals. The central thesis is that the significance of this axis is profoundly context-dependent, and its roles should be interpreted alongside the tumor’s underlying genomic status. Finally, we outline translational prospects, arguing that targeting this pathway will require precision medicine strategies, including composite biomarkers and rational combination therapies. These strategies should be tailored to the specific molecular subtype of each patient’s tumor.