LMO2 Regulates Epithelial-Mesenchymal Plasticity of Mammary Epithelial Cells

TL;DR

LMO2 helps maintain the balance between epithelial and mesenchymal states in mammary cells, and its loss promotes mesenchymal traits linked to cancer progression.

Contribution

This study reveals LMO2's novel role in regulating epithelial-mesenchymal plasticity in normal mammary epithelial cells.

Findings

LMO2 knockdown in mammary epithelial cells promotes mesenchymal differentiation.

LMO2 regulates epithelial cell state and its loss reduces organoid formation and regenerative capacity.

Transcriptional profiling shows LMO2 knockdown upregulates MCAM, a marker of mesenchymal transition.

Abstract

Cellular plasticity in mammary epithelial cells enables dynamic cell state changes essential for normal development but can be hijacked by breast cancer cells to drive tumor progression and metastasis. However, the molecular factors that maintain cellular plasticity through the regulation of a hybrid cell state (epithelial/mesenchymal) are not fully defined. As LMO2 has been previously shown to regulate metastasis in breast cancer, here we determine the role of LMO2 in normal mammary epithelial cells. Using lineage tracing and knockout mouse models, we find that Lmo2 lineage-traced cells are present in the luminal and basal layer of the mammary gland but have limited proliferative potential. Lmo2 loss does not impact mammary gland development, but acute deletion decreases in vivo reconstitution. Moreover, LMO2 knockdown in mouse and human mammary epithelial cells (MECs) reduces organoid formation. We find that LMO2 regulates the epithelial cell state in MECs and LMO2 knockdown promotes mesenchymal differentiation. Transcriptional profiling of LMO2 knockdown cells reveals significant enrichment in the epithelial-mesenchymal transition (EMT) pathway and upregulation of MCAM, a mesenchymal marker and negative regulator of regenerative capacity in the mammary gland. Altogether, we show that LMO2 plays a role in maintaining cellular plasticity in MECs, adding insight into the normal differentiation programs hijacked by cancer cells to drive tumor progression.

The online version contains supplementary material available at 10.1007/s10911-026-09598-8.

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