CDH1 loss remodels gene expression and lineage identity in human mammary epithelial cells.

Genetic CDH1 loss in human mammary epithelial cells remodels gene expression and lineage identity toward a luminal progenitor-like state, linked to increased proliferation and anoikis resistance.

• Why it matters: CDH1 loss defines invasive lobular carcinoma in ~95% of cases, but how early loss of E-cadherin signaling facilitates transformation is unclear.
• What they did: Finite-lifespan HMEC models were treated with antibody-mediated E-cadherin inhibition or genetic CDH1 loss via siRNA or CRISPR/Cas9 knockout, followed by transcriptome analysis across four models plus RNA-seq, single-cell transcriptomics, flow cytometry, microscopy, and ATAC-seq.
• The result: Antibody inhibition induced EMT signatures, whereas genetic CDH1 loss repressed EMT and remodeled toward luminal epithelial programs, mirrored in clinical ILC precursor lesions and producing luminal progenitor-like lineage homeostasis with enhanced proliferative capacity and anoikis resistance.