Abstract
Breast cancer (BCa) is the most frequently diagnosed malignancy in women worldwide, with approximately 70% of cases driven by oestrogen receptor alpha (ERα). Endocrine therapies aim to suppress ERα signalling activity and form the foundation of current therapeutic strategies. However, a substantial proportion of patients either fail to respond due to intrinsic resistance or acquire resistance over the course of the treatment. This resistance arises through a complex interplay of factors including crosstalk with other signalling pathways such as Notch. Notch signalling, essential for mammary gland development, is aberrantly activated in breast tumours, where it contributes to cancer stem cell maintenance, epithelial-mesenchymal transition, angiogenesis, and metastasis. Notch receptors exert context- and subtype-specific roles: Notch1 and 4 promote tumour aggressiveness, whereas Notch2 often exhibits tumour-suppressive roles. In ERα-positive BCa, ERα and Notch signalling cooperate to drive resistance, whereas in ERα-negative disease, Notch promotes stemness and angiogenesis. While anti-oestrogen therapies effectively inhibit tumour growth, they can paradoxically activate Notch signalling and promote therapeutic resistance. Co-targeting Notch alongside endocrine therapy has been proposed as a strategy to delay the onset of therapeutic resistance. However, clinical development of Notch inhibitors has been limited by toxicity associated with pan-Notch blockade. More selective approaches, such as paralogue-specific antibodies, transcription-complex disruption, rational drug combinations, and advanced delivery platforms, are under active development to overcome these limitations. This review outlines the ERα-Notch crosstalk in BCa and examines current and emerging strategies for targeting Notch to overcome endocrine resistance and improve clinical outcomes.