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ICAM2 promotes endocrine resistance via dynein-mediated OXPHOS activation in ER-positive breast cancer
Si Chen1,2, Shiyi Wu1,2, Jiajie Hu1,2
1Department of Clinical Laboratory & Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Acquired endocrine resistance in ER+ breast cancer (BC) involves metabolic reprogramming, yet key drivers are unclear. Multi-omics of endocrine-resistant BC revealed upregulated oxidative phosphorylation (OXPHOS) and identified intercellular adhesion molecule 2 (ICAM2) as a biomarker of high-OXPHOS cells. ICAM2-positive cells were significantly enriched in resistant tumors and predicted poor survival, and were functionally essential for maintaining resistance and promoting metastasis in vivo. Mechanistically, ICAM2 binds dynein light chain DYNLT3 and the mitochondrial complex I subunit MT-ND2, thereby facilitating dynein-mediated mitochondrial trafficking and further modulating the assembly of mitochondrial complex I. Disrupting this interaction through ICAM2 knockdown or dynein inhibition (Ciliobrevin D) effectively suppressed OXPHOS activity. Importantly, ERα inhibition alleviates the transcriptional repression of ICAM2 by ERα. Therapeutically, combining the complex I inhibitor IACS-10759 with fulvestrant potently inhibited both tumor growth and metastasis. Collectively, these findings reveal that ICAM2 drives endocrine resistance via dynein-dependent OXPHOS activation, revealing a targetable axis in refractory ER+ BC. In summary, we establish ICAM2 as a novel biomarker and driver of endocrine resistance in ER⁺ breast cancer. ICAM2⁺ cancer cells-enriched in treatment-resistant tumors-maintain elevated OXPHOS by assembling a functional complex with dynein and mitochondrial Complex I, thereby promoting mitochondrial trafficking. Disruption of this axis, either through ICAM2 depletion or Complex I inhibition, re-sensitizes tumors to therapy, revealing a targetable metabolic dependency in resistant disease.
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