Elevated GRHL2 Imparts Plasticity in ER-Positive Breast Cancer Cells

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2024 Aug 29

PMID 39199676

Authors

Christy Zheng

Kaelyn O Allen

Tianrui Liu

Natalia M Solodin

Mark B Meyer

Kelley Salem

Phillipos K Tsourkas

Sean J Mcilwain

Jessica M Vera

Erika R Cromwell

Mary Szatkowski Ozers

Amy M Fowler

Elaine T Alarid

Affiliations

Soon will be listed here.

Abstract

Estrogen receptor (ER)-positive breast cancer is characterized by late recurrences following initial treatment. The epithelial cell fate transcription factor Grainyhead-like protein 2 (GRHL2) is overexpressed in ER-positive breast cancers and is linked to poorer prognosis as compared to ER-negative breast cancers. To understand how GRHL2 contributes to progression, GRHL2 was overexpressed in ER-positive cells. We demonstrated that elevated GRHL2 imparts plasticity with stem cell- and dormancy-associated traits. RNA sequencing and immunocytochemistry revealed that high GRHL2 not only strengthens the epithelial identity but supports a hybrid epithelial to mesenchymal transition (EMT). Proliferation and tumor studies exhibited a decrease in growth and an upregulation of dormancy markers, such as and . Mammosphere assays and flow cytometry revealed enrichment of stem cell markers CD44 and ALDH1, and increased self-renewal capacity. Cistrome analyses revealed a change in transcription factor motifs near GRHL2 sites from developmental factors to those associated with disease progression. Together, these data support the idea that the plasticity and properties induced by elevated GRHL2 may provide a selective advantage to explain the association between GRHL2 and breast cancer progression.

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