Mitochondrial OXPHOS Induced by RB1 Deficiency in Breast Cancer: Implications for Anabolic Metabolism, Stemness, and Metastasis

A switch from catabolic to anabolic metabolism, a major hallmark of cancer, enables rapid cell duplication, and is driven by multiple oncogenic alterations, including PIK3CA mutation, MYC amplification, and TP53 loss. However, tumor growth requires active mitochondrial function and oxidative phosphorylation (OXPHOS). Recently, loss of the retinoblastoma (RB1) tumor suppressor in breast cancer was shown to induce mitochondrial protein translation (MPT) and OXPHOS. Here, we discuss how increased OXPHOS can enhance anabolic metabolism and cell proliferation, as well as cancer stemness and metastasis. Mitochondrial STAT3, FER/FER-T, and CHCHD2 are also implicated in OXPHOS. We propose that RB1 loss represents a prototypic oncogenic alteration that promotes OXPHOS, that aggressive tumors acquire lethal combinations of oncogenes and tumor suppressors that stimulate anabolism versus OXPHOS, and that targeting both metabolic pathways would be therapeutic. The impact of RB1 loss on MPT and OXPHOS is context dependent; RB1 loss represses MPT and OXPHOS in normal cells, but stimulates mitochondrial function in aggressive tumors. RB1 loss may represent a new class of oncogenic events, also including mitochondrial STAT3, FER/FER-T and CHCHD2, that promote mitochondrial function and OXPHOS and possibly tumor stemness and dissemination. RB1 deficiency increases sensitivity to inhibitors of mitochondrial protein translation (MPT) and OXPHOS.