High expression of apoptosis protein (Api-5) in chemoresistant triple-negative breast cancers: an innovative target.

// Guilhem Bousquet 1 , 2 , 3 , 6 , Jean-Paul Feugeas 4 , Yuchen Gu 1 , Christophe Leboeuf 1 , 2 , Morad El Bouchtaoui 2 , He Lu 2 , Marc Espie 5 , Anne Janin 1 , 2 , 7 and Melanie Di Benedetto 1 , 2 , 3 1 Universite Paris Diderot, Sorbonne Paris Cite, Laboratoire de Pathologie, UMR-S 1165, F-75010, Paris, France 2 INSERM, U942, F-75010, Paris, France 3 Universite Paris 13, Sorbonne Paris Cite, F-93000, Villetaneuse, France 4 INSERM, U1137-Paris, F-75018, France 5 AP-HP, Hopital Saint-Louis, Centre des Maladies du Sein, F-75010, Universite Paris Diderot, Sorbonne Paris Cite, INSERM CNRS UMR7212, Paris, France 6 AP-HP, Hopital Avicenne, Medical Oncology, F-93000, Bobigny, France 7 AP-HP, Hopital Saint-Louis, Laboratoire de Pathologie, F-75010, Paris, France Correspondence to: Melanie Di Benedetto, email: melanie.dibenedetto@univ-paris13.fr Guilhem Bousquet, email: guilhem.bousquet@aphp.fr Keywords: triple-negative breast cancer; chemotherapy resistance; apoptosis-inhibitor-5; peptide; anti-angiogenic therapy Received: June 29, 2019     Accepted: October 26, 2019     Published: November 12, 2019 ABSTRACT Anti-apoptotic protein-5 (API-5) is a survival protein interacting with the protein acinus, preventing its cleavage by caspase-3 and thus inhibiting apoptosis. We studied the effect of targeting API-5 in chemoresistant triple negative breast cancers (TNBCs), to reverse chemoresistance. 78 TNBC biopsies from patients with different responses to chemotherapy were analysed for API-5 expression before any treatment. Further studies on API-5 expression and inhibition were performed on patient-derived TNBC xenografts, one highly sensitive to chemotherapies (XBC-S) and the other resistant to most tested drugs (XBC-R). In situ assessments of necrosis, cell proliferation, angiogenesis, and apoptosis in response to anti-API-5 peptide were performed on the TNBC xenografts. Clinical analyses of the 78 TNBC biopsies revealed that API-5 was more markedly expressed in endothelial cells before any treatment among patients with chemoresistant TNBC, and this was associated with greater micro-vessel density. A transcriptomic analysis of xenografted tumors showed an involvement of anti-apoptotic genes in the XBC-R model, and API-5 expression was higher in XBC-R endothelial cells. API-5 expression was also correlated with hypoxic stress conditions both in vitro and in vivo . 28 days of anti-API-5 peptide efficiently inhibited the XBC-R xenograft via caspase-3 apoptosis. This inhibition was associated with major inhibition of angiogenesis associated with necrosis and apoptosis. API-5 protein could be a valid therapeutic target in chemoresistant metastatic TNBC.