All-trans retinoic acid and protein kinase C alpha/beta 1 inhibitor combined treatment targets cancer stem cells and impairs breast tumor progression

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 PKC alpha together with high RAR alpha 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.

Automated summary

In the treatment of breast cancer, the combination of all-trans-retinoic acid (ATRA) and the classical PCK inhibitor Go6976 significantly reduces tumor proliferative potential and increases apoptosis rate, promoting an anti-oncogenic profile. Additionally, the combined treatment reduces the growth, self-renewal, and clonogenicity of cancer stem cells, leading to decreased tumor growth, metastatic spread, and cancer stem cells frequency.