HER3 in breast cancer: molecular insights, clinical implications, and therapeutic horizons

erb-b2 receptor tyrosine kinase 3 (ERBB3/HER3) a kinase-inactive HER family receptor, significantly influences breast cancer by enhancing oncogenic signaling mainly via HER2 heterodimerization. Its role in therapy resistance marks it as a key target across subtypes, tackling a critical oncology challenge. This review delves into HER3's molecular structure, with its ligand-binding extracellular domain and tyrosine-rich tail activating PI3K/AKT and MAPK/ERK pathways. It examines HER3's impact on tumor progression - like invasion and metastasis - and resistance to therapies such as trastuzumab, endocrine treatments, and chemotherapy across HER2- positive, hormone receptor-positive, and triple-negative subtypes, based on extensive literature. Clinically, it assesses HER3's prognostic role, with overexpression in 30-50% of cases, and therapeutic advances, notably antibody-drug conjugates (ADCs) like patritumab deruxtecan, promising in trials. HER3's therapeutic potential is transformative, with ADCs and combinations poised to redefine personalized care by improving survival in resistant cases. Its overexpression offers a strategic leverage point, yet inconsistent detection and adaptive resistance pose barriers. These demand innovative solutions, such as refined diagnostics and multi-target therapies. Given its demonstrated efficacy, HER3-targeted therapies, supported by novel therapeutic combinations and bioengineering innovations, are expected to become integral to routine clinical practice in the coming years, advancing precision oncology.