PATZ1 Restrains Basal-like Breast Cancer Aggressiveness while Preserving FOXA1-Driven Luminal Identity

Abstract Breast cancer comprises biologically distinct subtypes characterized by differences in lineage identity, tumor aggressiveness, and therapeutic response. However, the transcriptional mechanisms governing subtype specification and cellular plasticity remain incompletely understood. Here, we identify PATZ1 as a key regulator of luminal identity and phenotypic plasticity in breast cancer. Integrative analyses of The Cancer Genome Atlas and independent transcriptomic datasets revealed that PATZ1 expression is enriched in luminal breast cancers, positively correlates with FOXA1 expression, and associates with lower tumor grade and improved patient outcome. Mechanistically, chromatin immunoprecipitation, promoter-reporter, and loss-of-function assays demonstrated that FOXA1 is a direct transcriptional target of PATZ1 in luminal breast cancer cells. Functional studies in the Basal B/triple-negative breast cancer cell line MDA-MB-231 showed that PATZ1 overexpression promotes luminal epithelial reprogramming, characterized by increased KRT8 and EpCAM expression and reduced CD44 levels, while significantly suppressing proliferation, migration, invasion, and anchorage-independent growth. In addition, conditioned medium from Patz1-deficient fibroblasts induced transcriptional reprogramming in luminal MCF7 cells, downregulating the luminal epithelial markers CDH1 and KRT8 and, notably, PATZ1 itself, while increasing SOX2 and IL6 expression, consistent with loss of luminal identity and enhanced cellular plasticity. Collectively, our findings identify PATZ1 as a key regulator of breast cancer cell identity and phenotypic plasticity, integrating tumor-intrinsic control of luminal differentiation with microenvironment-dependent signaling and providing a conceptual framework for understanding- and potentially limiting - the plasticity that fuels breast cancer progression.