Subtype-Specific Transcriptional and Metabolic Liabilities in Breast Cancer

Objective: Breast cancer is routinely stratified in clinical practice according to estrogen receptor (ER), progesterone receptor (PR), and HER2 expression profiles. However, the functional gene dependencies that sustain each breast cancer subgroup remain incompletely defined. This study aimed to map subtype-associated functional vulnerabilities in breast cancer. Materials and Methods: Using DepMap CRISPR gene essentiality scores, breast cancer cell lines were classified into TNBC, HER2-positive, and ER/PR-positive cohorts. Subtype dependencies were compared via two-sided Wilcoxon rank-sum tests and median score deltas. Additionally, TNBC models were stratified into Basal A and B states to capture functional diversity. Results: ER/PR-positive cell lines exhibited strong dependency on lineage-associated transcriptional regulators, complemented by patient-level enrichment of LDB1 in luminal tumors. TPK1 emerged as a vulnerability in HER2-amplified models, with patient data validating its broader expression across non-luminal subtypes alongside TBL1XR1. Within TNBC, Basal A models were associated primarily with cytokinetic and mitochondrial functions; whereas, Basal B models showed greater dependence on cell–matrix interaction pathways, with ITGAV among the most prominent subtype-selective vulnerabilities. Conclusion: Breast cancer subtypes exhibit distinct functional vulnerabilities beyond receptor status alone, supporting dependency landscapes for refining stratification and prioritizing therapeutic targets.