Shahrouzi, P.; Azimzade, Y.; Brankiewicz, W.; Bhatia, S.; Kunke, D.; Richard, D.; Tekpli, X.; Kristensen, V. N.; Duijf, P. H. G.

Breast cancer (BCa) is a major global health challenge, characterized by chromosomal instability (CIN) and subsequent acquisition of extensive somatic copy number alterations (CNAs). CNAs including amplifications and deletions, significantly influence intra-tumor heterogeneity and the tumor microenvironment (TME). Among these, the loss of chromosome 13q14.2 emerges as a considerable factor in BCa pathogenesis and treatment responses. We provide evidence that this genomic alteration is under positive selective pressure, correlating with poorer patient survival. Furthermore, through multi-omic and in vitro analyses, we uncover a dual role of 13q14.2 loss: it confers a survival advantage to tumor cells and modulate the cell cycle and pro-apoptotic pathways in cancer cells, affecting macrophages population in the TME, while paradoxically increasing tumor susceptibility to BCL2 inhibitors. These findings suggest that targeting 13q14.2 as a biomarker in BCa could enhance the efficacy of existing treatments and offer a new avenue for improving clinical outcomes in BCa.