Activin A signaling in breast cancer: context-dependent reweighting of cytostatic, metastatic and immunomodulatory outputs

Activin A, a homodimeric ligand encoded by INHBA, is a pleiotropic member of the transforming growth factor-β superfamily whose effects in breast cancer depend on cellular and microenvironmental context. This review examines how ligand abundance and bioavailability, receptor composition, SMAD competence, transcriptional context, cellular source and the tumor microenvironment shape activin A signaling outputs. Importantly, INHBA expression, activin A protein abundance, extracellular ligand bioavailability and functional pathway activation represent distinct biological levels and should not be considered interchangeable. In selected epithelial contexts, activin A supports SMAD-dependent cytostasis and cell-cycle arrest, whereas in progression-associated contexts it is linked to epithelial plasticity, invasion, stem-like phenotypes, metastatic dissemination, stromal remodeling and immune regulation. We propose that the apparent activin A “signaling switch” represents context-dependent reweighting of signaling outputs rather than a binary molecular transition. Direct breast cancer evidence is strongest for cytostatic, EMT-associated and invasive phenotypes, whereas evidence for pro-angiogenic signaling, MMP2-dependent remodeling and some immunomodulatory effects remains more limited or context dependent. Activin A may also contribute to pulmonary metastatic progression through tumor-cell-intrinsic signaling and systemic conditioning of the lung microenvironment. Clinically, INHBA and activin A show prognostic or contextual associations but have not been validated as predictive biomarkers or therapeutic targets in breast cancer. Future studies should prioritize functional, cell-type-resolved and spatial biomarker strategies to distinguish cytostatic activin signaling from progression-associated activity.