Abstract
Genetic background can alter the latency and behavior of cancers initiated by the same oncogenic driver, but how inherited variation reshapes the regulatory landscape that permits tumor development remains poorly understood. The PWK genetic background accelerates mammary tumor onset in the NeuT model. We compared PWK NeuT and BALB NeuT tumors using tumor-level RNA-seq, histone ChIP-seq, and single-cell multiome profiling. PWK tumors exhibited broad transcriptional reprogramming characterized by reduced immune-associated expression and increased epithelial differentiation and neuronal-like programs. Chromatin remodeling was spatially redistributed rather than uniformly increased or decreased. PWK tumors showed expansion of H3K9me3- and H4K20me3-associated chromatin, while both marks were depleted across many expressed genes and concentrated within selected intergenic and repeat-rich territories, revealing coordinated redistribution of constitutive heterochromatin. Single-cell multiome profiling showed that broad epithelial representation remained similar between strains, yet specific malignant states were strongly strain biased. Integrated RNA and accessibility analyses identified concordant strain-selective regulatory programs and candidate loci, while trajectory analysis revealed distinct epithelial state transitions between PWK NeuT and BALB NeuT tumors. Together, these findings indicate that inherited genetic background reshapes transcriptional programs, heterochromatin organization, and malignant epithelial state trajectories in NeuT mammary tumors, providing a regulatory framework for understanding strain-dependent differences in tumor onset.