PRKAR2A/RIIα as a candidate spatial cAMP-PKA signal router in triple-negative breast cancer metastasis: evidence boundaries, competing models and decisive experiments.

Abstract

Metastatic relapse remains the principal lethal event in triple-negative breast cancer (TNBC), yet the contribution of PRKAR2A, which encodes the type IIα regulatory subunit (RIIα) of protein kinase A (PKA), remains unresolved. RIIα creates a mechanistic duality: it restrains catalytic PKA within the holoenzyme while recruiting type II PKA to A-kinase anchoring protein (AKAP) microdomains. A targeted critical narrative search identified no eligible published study in the searched sources that causally linked PRKAR2A to a TNBC metastasis endpoint. Direct evidence is limited to four association or detection contexts: PRKAR2A mRNA differed at the adjusted-significance boundary between pathological complete response and residual disease but was not retained in the final consensus predictor; its transcript was induced in a lipid-adapted TNBC heterospheroid state without gene-specific perturbation; RIIα was detected in mitochondria-endoplasmic-reticulum contact fractions whose local PKA activity controlled calcium transfer and apoptosis without isolating RIIα; and PRKAR2A entered a multigene prognostic signature without independent or cell-resolved validation. AKAP2 depletion altered focal-adhesion signalling, invasion, primary-tumour growth and lung signal, but neither the operative PKA regulatory subunit nor a burden-independent metastatic effect was established. These boundaries support four competing interpretations: PRKAR2A may be a driver, compensatory brake, localisation determinant or passenger state marker. Decisive tests require inducible depletion, near-endogenous domain-resolved rescue, compartment-targeted PKA reporters, endogenous complex mapping and stage-resolved metastasis assays. Until then, RIIα is best treated as a candidate spatial signal router rather than a validated biomarker or therapeutic target.