All-Trans Retinoic Acid and Protein Kinase C α/β1 inhibitor combined treatment targets cancer stem cells and impairs breast tumor progression

BERARDI; ARIZA BAREÑO; AMIGO; CAÑONERO; PELAGATTI; MOTTER; TARUSELLI; DÍAZ BESSONE; CIRIGLIANO; EDELSTEIN; PETERS; DIAMENT; URTREGER; TODARO

Scientific Reports

Nature

Lugar: Londres; Año: 2021 vol. 11

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 (Gö6976) in preclinical settings. Employing hormone-independent mammary cancer models, Gö6976 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 PKCα together with high RARα 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.