All-trans retinoic acid and protein kinase C a/b1 inhibitor combined treatment targets cancer stem cells and impair breast tumor progression

DAMIAN E. BERARDI; LIZETH ARIZA BAREÑO; NATALIA AMIGO; LUCIANA CAÑONERO; MARIA DE LAS NIEVES PELAGATTI; ANDREA NORA MOTTER; MARÍA AGUSTINA TARUSELLI; MARIA I. DIAZ BESSONE; STÉFANO M. CIRIGLIANO; ALEXIS EDELSTEIN; MARÍA GISELLE PETERS; MIRIAM DIAMENT; ALEJANDRO J. URTREGER; LAURA B. TODARO

Scientific Reports

Nature Publishing Group

Lugar: Londres; Año: 2021 vol. 11 p. 6044 - 6061

2045-2322

ULTIMA AUTORIA COMPARTIDA.Breast cancer is the leading cause of cancer death among women worldwide. Blocking a single signaling pathway is often an ineffective therapy, especially in the case of aggressive or drug-resistant tumors. Since we have previously described the mechanism involved in the crosstalk between Retinoic Acid system and protein kinase C (PKC) Pathway, the rationale of our study was to evaluate the effect of Combining all-trans-retinoic acid (ATRA) with a classical PCK inhibitor (Go6976) in preclinical settings. Employing hormone-independent mammary cancer models, Go6976 and ATRA combined treatment induced a synergistic reduction in proliferative potential that correlated with an increased apoptosis and RARs modulation towards an anti-oncogenic profile. Combined treatment also impairs growth, 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?Meier plotter? database indicated that low PKCa together with high RARa mRNA expression is a favorable prognosis factor for hormone-independent breast cancer patients. Here we demonstrate that a classical PKC inhibitor potentiates ATRA antitumor effects also targeting cancer stem cells growth, self-renewal and frequency.