Estrogen receptor alpha dynamics and plasticity during endocrine resistance

Area of Science:

• Molecular biology
• Cancer research
• Cell biology

Background:

• Breast cancer is classified into subtypes based on hormone receptor (HR) and HER2 status.
• ERα-positive breast cancer patients often develop resistance to endocrine therapy, leading to metastasis.
• Spatio-temporal changes and loss of ERα under treatment pressure are significant clinical challenges.

Purpose of the Study:

• To investigate the mechanisms underlying ERα plasticity and heterogeneity in breast cancer cells.
• To understand how ERα expression changes in response to endocrine treatment.
• To explore the role of ERα in tumor progression and treatment resistance.

Main Methods:

• Engineered triple-negative breast cancer cells to express EGFP-ERα for live-cell imaging.
• Analyzed ERα expression changes in response to 4-hydroxytamoxifen and endoxifen.
• Utilized RNA sequencing to identify signaling pathways regulated by ERα.
• Assessed ERα expression heterogeneity using cell cycle indicator probes in 2D and 3D cultures.

Main Results:

• In vitro resistance correlated with ERα downregulation; however, initial endocrine treatment upregulated ERα, potentially via proteasome or autophagy pathways.
• Inhibition of autophagy and proteasome enhanced ERα expression.
• RNA sequencing revealed ERα regulates ubiquitin, proteasome pathways, cell proliferation, and Unfolded Protein Responses (UPR).
• ERα expression heterogeneity was observed in a cell cycle phase-independent manner in both 2D and 3D cultures.

Conclusions:

• The study confirms intrinsic post-transcriptional mechanisms drive ERα plasticity.
• ERα plasticity may contribute to receptor heterogeneity and tumor progression during endocrine therapy.
• Further investigation into these mechanisms is warranted for therapeutic development.