Cis‐regulatory and long noncoding <scp>RNA</scp> alterations in breast cancer – current insights, biomarker utility, and the critical need for functional validation

Breast cancer's global prevalence underscores a critical need for novel biomarkers to guide treatment and improve patient outcomes. Biomarker discovery historically focused on mutations in protein coding regions, comprising merely 1% of the genome. However, with advances in whole-genome sequencing, the functional significance of the noncoding genome-comprising the remaining 99%-has become increasingly evident. Noncoding regions play a vital role in regulating gene expression, and mutations within these regions have been associated with cancer risk, progression, and treatment response. This Review compiles and synthesizes current knowledge on cis-regulatory alterations (promoters/enhancers) and long noncoding RNAs (lncRNAs) in breast cancer. Key examples include promoter mutations [e.g., rs2279744 (Mouse double minute 2 homolog gene; MDM2)], enhancer mutations [e.g., rs4784227 (thymocyte selection-associated high mobility group box family member 3 gene; TOX3)], and lncRNAs [e.g., HOX transcript antisense intergenic RNA (HOTAIR)] linked to progression, metastasis, and poor survival. Integrating preclinical (in vitro, in vivo) and clinical findings, we emphasize the biomarker and therapeutic potential of these noncoding alterations. This Review also critically identifies the pressing need for more specific functional validation studies to fully elucidate their mechanistic roles. This emerging field offers promising opportunities to advance personalized medicine and refine prognostic/predictive strategies for breast cancer patients.