Transcriptional silencing of homologous recombination defines a functional HRD in invasive lobular carcinoma

Background: Homologous recombination deficiency (HRD) is a key determinant of genomic instability and a major predictor of PARP inhibitor (PARPi) sensitivity in breast cancer. While invasive ductal carcinoma (IDC) commonly exhibits canonical HRD driven by BRCA1/2 loss and characteristic genomic scars, the HR status of invasive lobular carcinoma (ILC) remains poorly characterized. Recent evidence suggests that a subset of ILC displays a BRCAness-like phenotype undetected by conventional genomic HRD scores, implying a transcriptionally driven functional HRD mechanism. Methods: RNA-sequencing data from TCGA-BRCA were analyzed by integrating genomic HRDsum scores with ssGSEA-based pathway scores for a curated HR gene set. Samples were stratified by histological subtype (IDC vs. ILC) and ranked by PARPi7, a seven-gene transcriptomic signature predictive of PARPi response. Correlation analyses and linear interaction models were applied to examine subtype-specific relationships among PARPi7, genomic HRDsum, and HR pathway activity. Differential expression and upstream regulator analyses were performed to identify transcriptomic features and regulators associated with functional HRD in ILC. Results: In IDC, PARPi7 correlated positively with HRDsum (R = 0.34) and negatively with estrogen receptor expression, consistent with the classical triple-negative breast cancer-like genomic HRD phenotype. HR pathway activity showed minimal association (R = -0.07), supporting a genomically driven HRD. In ILC, this pattern was reversed: PARPi7 correlated negatively with HRDsum (R = -0.20) and strongly with HR pathway suppression (R = -0.48), suggesting that transcriptional silencing of HR genes underlies a functional HRD phenotype in ILC. PARPi7-high ILC tumors exhibited coordinated downregulation of DNA repair and cell-cycle programs with concurrent inflammatory and immune activation. BRCA1 expression was reduced in both subtypes but more markedly in IDC (adj.P = 9.29×10⁻⁸¹ vs 1.47×10⁻¹⁸). Upstream regulator analysis identified selective activation of NUPR1 in PARPi7-high ILC - a stress-responsive transcriptional regulator linked to PARP activity and tolerance to DNA damage. Conclusion: While PARPi7-high IDC reflects canonical, genomically driven HRD with BRCA1-type biology, ILC demonstrates a transcriptionally defined functional HRD lacking genomic scars, implying that PARPi7-high behavior can emerge even in genomically HRD-low tumors. This phenotype involves transcriptional suppression of HR genes and DNA repair machinery, low HRDsum, inflammatory activation, and NUPR1-mediated stress adaptation. These findings define a transcriptomic axis of functional HRD in ILC, suggesting expansion of PARPi strategies beyond genomic HRD to include HR pathway silencing and NUPR1 activation as biomarkers of therapeutic sensitivity.