Insulin-like Growth Factor-1 (IGF-1) is a crucial mitogenic factor with important functions in the mammary gland, mainly through its interaction with the IGF-1 receptor (IGF-1R). This interaction activates a complex signaling network that promotes cell proliferation, epithelial to mesenchymal transition (EMT) and inhibits apoptosis. Despite extensive research, the precise molecular pathways and intracellular mechanisms activated by IGF-1, in cancer, remain poorly understood. Recent evidence highlights the essential roles of IGF-1 and its isoforms in breast cancer (BC) development, progression, and metastasis. The peptides that define the IGF-1 isoforms—IGF-1Ea, IGF-1Eb, and IGF-1Ec—act as key points of convergence for various signaling pathways that influence the growth, metastasis and survival of BC cells. The aim of this review is to provide a detailed exami-nation of the role of the mature IGF-1 and its isoforms in BC biology and their potential use as possible therapeutical targets.

Breast cancer (BC) is increasingly recognized as a heterogeneous disease, with complexity that extends beyond the classical luminal A/B, HER2-enriched, and triple-negative framework. Advances in molecular and functional profiling have uncovered emerging subpopulations, including HER2-low, claudin-low, BRCA-deficient (“BRCAness”), and refined TNBC subsets, such as luminal AR (LAR) and basal-like immune variants, that extend beyond traditional taxonomies. These novel classifications provide additional resolutions, offering both prognostic insight and therapeutic opportunities. In this comprehensive review, we integrate evidence from genomic, epigenetic, proteomic, immune-related, and liquid biopsy biomarkers, underscoring how they define the biology of these subgroups and predict responses to targeted therapies, such as antibody–drug conjugates, PARP inhibitors, and immune checkpoint blockade. We further highlight the role of the tumor microenvironment (TME) and intratumoral heterogeneity in shaping these entities. Collectively, recognition of emerging subtypes as clinically actionable groups represents a paradigm shift from static receptor-based models to dynamic, biomarker-driven frameworks that refine prognosis, enable patient stratification, and support precision oncology in aggressive BC.

The IGF-1Eb isoform has been proposed as a stress-responsive variant of IGF-1, yet its significance in cancer remains unclear. This investigation aims to clarify its role across breast, prostate and liver cancer cell lines and determine whether its loss or supplementation is associated with alterations in cellular behavior and stress adaptation. Eb expression was modulated through targeted silencing and exogenous peptide addition. Cellular responses were evaluated under normal conditions and UV stress using proliferation, viability and rescue experiments, wound healing, immunofluorescence for Eb-knockdown confirmation, qRT-PCR, Annexin V/PI apoptosis, and PI cell-cycle evaluation. Across six cancer cell lines, Eb peptide given before UV stress was associated with partial protective effects, whereas post-UV treatment was associated with improved recovery and partial restoration of proliferative capacity. The rescue effect differed by cell type, with prostate and breast cells showing the strongest responses and liver-derived lines displaying more modest improvements. Eb knockdown revealed clear cell-type-specific dependencies. PC3 cells showed markedly reduced proliferation (p < 0.01) and sharply decreased post-UV viability (p < 0.0001). HepG2 cells maintained higher growth without UV but displayed reduced recovery following UV exposure, whereas MDA-MB-231 exhibited elevated apoptosis (p < 0.05) with limited additional UV sensitivity. Eb peptide may exert a dual, timing-dependent role, supporting protection before UV damage and facilitating recovery-associated responses afterward, with its impact differing across cell lines.