Elevated GRHL2 Imparts Plasticity in ER-Positive Breast Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Estrogen receptor (ER)-positive breast cancer frequently exhibits late recurrences.
• Grainyhead-like protein 2 (GRHL2), a transcription factor, is overexpressed in ER-positive breast cancers, correlating with worse prognosis.

Purpose of the Study:

• To investigate how elevated GRHL2 expression contributes to the progression of ER-positive breast cancer.
• To elucidate the cellular and molecular mechanisms by which GRHL2 influences cancer cell behavior.

Main Methods:

• Overexpression of GRHL2 in ER-positive breast cancer cells.
• RNA sequencing and immunocytochemistry for molecular profiling.
• Proliferation and tumor growth studies.
• Mammosphere assays and flow cytometry for stem cell marker analysis.
• Cistrome analyses to identify transcription factor binding changes.

Main Results:

• Elevated GRHL2 expression induced cell plasticity, stem cell traits, and dormancy markers (e.g., NR2F1, CDKN1B).
• High GRHL2 maintained epithelial identity while supporting a hybrid epithelial-to-mesenchymal transition (EMT).
• GRHL2 overexpression enriched stem cell markers (CD44, ALDH1) and increased self-renewal capacity.
• Cistrome analysis revealed altered transcription factor binding motifs associated with disease progression.

Conclusions:

• Elevated GRHL2 in ER-positive breast cancer promotes cellular plasticity and stem-like properties.
• These GRHL2-induced traits may confer a selective advantage, contributing to late recurrences and poorer outcomes.
• GRHL2's role in maintaining a hybrid epithelial/mesenchymal state and dormancy is crucial for breast cancer progression.