Loss of CDH1 rewires mammary cell identity toward a luminal progenitor state

Loss of the gene CDH1, which encodes the cell adhesion protein E-cadherin, remodels gene expression and lineage identity in human mammary epithelial cells, shifting them toward a luminal progenitor-like state, according to a new study in PLOS Genetics.

Invasive lobular carcinoma (ILC), a common subtype of breast cancer, is molecularly defined by genetic loss of CDH1 and subsequent loss of E-cadherin in about 95% of cases. Although CDH1 loss occurs early in ILC oncogenesis, how it facilitates transformation has remained unclear.

To model this early event, researchers used finite-lifespan “normal” human mammary epithelial cells (HMECs) reflecting early hyperplasia. They targeted E-cadherin in two distinct ways: blocking cell-cell contacts with antibodies, or causing genetic CDH1 loss using siRNA or CRISPR/Cas9 knockout.

Transcriptome analysis across four HMEC models showed that the mode of E-cadherin targeting critically shaped the resulting phenotype. Antibody-mediated disruption of cell-cell contacts induced gene signatures of epithelial-mesenchymal transition (EMT), consistent with the known role of E-cadherin suppression during EMT.

Genetic CDH1 loss, as occurs in ILC oncogenesis, produced the opposite pattern: it repressed EMT signatures and instead remodeled gene expression toward a luminal epithelial phenotype.

Multiple independent methods supported this conclusion. RNA-seq, single-cell transcriptomics, flow cytometry, microscopy, and ATAC-seq analyses all indicated that CDH1 loss induces lineage remodeling toward a luminal state, a pattern mirrored in transcriptomic analysis of clinical ILC precursor lesions.

By isolating luminal and basal cells before CDH1 knockout, the team found that CDH1 loss remodeled lineage identity in both populations, with the two converging on a new lineage homeostasis characterized by a luminal progenitor-like phenotype.

Consistent with this shift, CDH1 loss enhanced proliferative capacity over the finite lifespan of the HMECs, a feature the authors suggest may contribute to clonal advantage during tumor initiation. CDH1 loss also enhanced anoikis resistance, a defining feature of ILC cells.

The findings support the idea that genetic loss of CDH1 in mammary epithelial cells drives transcriptional and phenotypic changes consistent with remodeling toward a luminal progenitor-like state, which may underpin how early CDH1 loss mediates ILC oncogenesis. Because the work was conducted in cell culture models of early hyperplasia rather than in patients, the results represent mechanistic modeling of an early oncogenic event rather than direct clinical evidence.

Subject of Research: How CDH1 loss remodels gene expression and lineage identity in human mammary epithelial cells

Article Title: CDH1 loss remodels gene expression and lineage identity in human mammary epithelial cells

Article References: Musick, M., Ufondu, C. A., Rowland, C. E., Brown, M. E., Sottnik, J. L., Shackleford, M. T., Nesiba, C. S., Danis, E. P., Goodspeed, A. E., Zera, R., Johnson, A. T., Schwertfeger, K. L., Nelson, A. C., Ostrander, J. H., & Sikora, M. J. (2026). CDH1 loss remodels gene expression and lineage identity in human mammary epithelial cells. PLOS Genetics, 22(10), e1012351. https://doi.org/10.1371/journal.pgen.1012351

Image Credits: AI Generated

DOI: 10.1371/journal.pgen.1012351

Keywords: CDH1, E-cadherin, invasive lobular carcinoma, human mammary epithelial cells, luminal progenitor, lineage remodeling, EMT, CRISPR, ATAC-seq, breast cancer, loss, remodels