Oncotarget

Research Papers:

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

Guilhem Bousquet _, Jean-Paul Feugeas, Yuchen Gu, Christophe Leboeuf, Morad El Bouchtaoui, He Lu, Marc Espié, Anne Janin and Melanie Di Benedetto _

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Oncotarget. 2019; 10:6577-6588. https://doi.org/10.18632/oncotarget.27312

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Abstract

Guilhem Bousquet1,2,3,6, Jean-Paul Feugeas4, Yuchen Gu1, Christophe Leboeuf1,2, Morad El Bouchtaoui2, He Lu2, Marc Espié5, Anne Janin1,2,7 and Melanie Di Benedetto1,2,3

1 Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, F-75010, Paris, France

2 INSERM, U942, F-75010, Paris, France

3 Université Paris 13, Sorbonne Paris Cite, F-93000, Villetaneuse, France

4 INSERM, U1137-Paris, F-75018, France

5 AP-HP, Hôpital Saint-Louis, Centre des Maladies du Sein, F-75010, Université Paris Diderot, Sorbonne Paris Cité, INSERM CNRS UMR7212, Paris, France

6 AP-HP, Hôpital Avicenne, Medical Oncology, F-93000, Bobigny, France

7 AP-HP, Hôpital 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.


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