Keratin 18 as a Regulator of Estrogen Receptor α Signaling

Review Article

Keratin 18 as a Regulator of Estrogen Receptor α Signaling

Aino Virtanen*

Department of Clinical Genetics, University of Helsinki, Helsinki, Finland

Abstract

Estrogen receptor α (ERα) is a critical transcription factor that mediates estrogen signaling in mammary epithelial cells and plays a pivotal role in the progression of estrogen-dependent breast cancers. The identification of regulatory cofactors that modulate ERα function is essential for understanding breast cancer biology and developing targeted therapies. Leukemia-related protein 16 (LRP16) has emerged as both a transcriptional target and coactivator of ERα, forming a positive feedback loop that enhances estrogen-dependent gene transcription and cellular proliferation. The nuclear localization of LRP16 is essential for its coactivator function. Recent studies have uncovered a novel regulatory mechanism wherein the cytoplasmic intermediate filament protein Keratin 18 (K18) interacts with LRP16 and modulates its subcellular localization. The overexpression of K18 in MCF-7 breast cancer cells leads to the sequestration of LRP16 in the cytoplasm, thereby diminishing its nuclear presence and weakening its interaction with ERα. This cytoplasmic trapping of LRP16 attenuates ERα-driven transcription and suppresses estrogen-induced cell cycle progression. Conversely, knockdown of K18 enhances LRP16 nuclear localization, increasing ERα activity and promoting S-phase entry. These findings reveal a critical cytoplasmic checkpoint mediated by K18 that modulates the transcriptional output of ERα by controlling the availability of its coactivator LRP16. Understanding this regulatory interplay between K18, LRP16, and ERα not only highlights the importance of subcellular localization in hormone receptor signaling but also presents a potential therapeutic axis for modulating estrogen responsiveness in breast cancer.

Keywords: Estrogen receptor alpha; LRP16; Keratin 18; Breast cancer; Coactivator sequestration; Subcellular localization; Estrogen signaling