All‑trans retinoic acid and protein kinase C α/β1 inhibitor combined treatment targets cancer stem cells and impairs breast tumor progression

DAMIAN EMILIO BERARDI; LIZETH ARIZA BAREÑO; NATALIA AMIGO; LUCIANA CAÑONERO; MARIA DE LAS NIEVES PELAGATTI; ANDREA NORA MOTTER; MARÍA AGUSTINA TARUSELLI; MARÍA INÉS DÍAZ BESSONE; STEFANO MARTIN CIRIGLIANO; ALEXIS EDELSTEIN; MARÍA GISELLE PETERS; MIRIAM DIAMENT; ALEJANDRO JORGE URTREGER; LAURA BEATRIZ TODARO

Scientific Reports

Nature

Año: 2021

2045-2322

Breast cancer is the leading cause of cancer death among women worldwide. Blocking a singlesignaling pathway is often an ineffective therapy, especially in the case of aggressive or drug-resistanttumors. Since we have previously described the mechanism involved in the crosstalk between RetinoicAcid system and protein kinase C (PKC) pathway, the rationale of our study was to evaluate theeffect of combining all-trans-retinoic acid (ATRA) with a classical PCK inhibitor (Gö6976) in preclinicalsettings. Employing hormone-independent mammary cancer models, Gö6976 and ATRA combinedtreatment induced a synergistic reduction in proliferative potential that correlated with an increasedapoptosis and RARs modulation towards an anti-oncogenic profile. Combined treatment also impairsgrowth, self-renewal and clonogenicity potential of cancer stem cells and reduced tumor growth,metastatic spread and cancer stem cells frequency in vivo. An in-silico analysis of ?Kaplan?Meierplotter? database indicated that low PKCα together with high RARα mRNA expression is a favorableprognosis factor for hormone-independent breast cancer patients. Here we demonstrate that aclassical PKC inhibitor potentiates ATRA antitumor effects also targeting cancer stem cells growth,self-renewal and frequency.