The estrogen-integrin αvβ3 crosstalk in breast cancer: Modulating PD-L1 and immune evasion.

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.