The estrogen-integrin αvβ3 crosstalk in breast cancer: Modulating PD-L1 and immune evasion.
TL;DR
A novel "dual-track" regulatory model is proposed to resolve the conflicting roles of estrogen in tumor immunity and novel molecular targets are uncovered to improve combined endocrine and immunotherapeutic regimens for breast cancer patients.
Abstract
The mechanisms governing PD-L1 expression in breast cancer are highly complex and context-dependent. This article proposes a novel "dual-track" regulatory model to resolve the conflicting roles of estrogen in tumor immunity. Genomic signaling through ER-α suppresses PD-L1 transcription, explaining lower PD-L1 levels in ER-α-positive tumors. Conversely, non-genomic signaling mediated by cell-surface integrin αvβ3 drives PD-L1 presentation by triggering downstream PI3K/Akt and MAPK/ERK 1/2 pathways. We synthesize emerging data on how post-translational modulators (RNF31, p66Shc) and metabolic regulators (SIRT1-NAD+ axis) fine-tune PD-L1 stability. This interplay reveals a therapeutic vulnerability: antiestrogen treatments can paradoxically increase surface PD-L1 expression. In triple-negative breast cancer (TNBC), the absence of ER-α combined with active integrin αvβ3 signaling accelerates PD-L1-mediated immune evasion. This comprehensive framework uncovers novel molecular targets to improve combined endocrine and immunotherapeutic regimens for breast cancer patients.