Role of Mitochondrial DNA Polymerase gamma (POLG) in Breast Cancer

Chinigo, Chiara

Abstract

Breast cancer is the most frequent malignancy in women and represents one of the driving
causes of death from cancer, worldwide. In this scenario, targeUng tumor heterogeneity
could present important therapeuUcal implicaUons. Indeed, neoplasUc breast Ussue is
characterized by a “cell hierarchy” whereby a sub-populaUon of cells with “stemness”
characterisUcs, termed breast cancer stem cells (BCSCs), has the ability to self-renew and
is considered the main driver of drug-resistance and metastasis. Recently, mitochondria
have been shown to be key players in breast cancer stem cells biology. Many metabolic
pathways, such as mitochondrial oxidaUve phosphorylaUon (OXPHOS) and mitochondrial
biogenesis, are dysfuncUonal during tumorigenesis, highlighUng a key role of these
organelles in breast cancer pathogenesis. For example, there is a need for further clarity
how the crosstalk between nuclear gene(s) and mitochondrial DNA, affect mitochondrial
DNA replicaUon, mitochondrial OXPHOS, and BCSCs acUvity. In this context, the
mitochondrial DNA Polymerase-γ (POLG), which is composed by a single catalyUc subunit
codified by the nuclear gene POLG1 and a dimeric accessory subunit codified by nuclear
gene POLG2, is the only DNA-polymerase present in human mitochondria and plays a
crucial role in mitochondrial DNA (mt-DNA) replicaUon and repair, by regulaUng mt-DNA
copy number in BCSCs. Thus, the overall aim of this research project is to inhibit
mitochondrial DNA replicaUon using POLG genes as a target, using both a geneUc and a
pharmacological approach, and to evaluate chemical strategies in order to idenUfy new
mitochondrial-targeUng agents aimed to specifically inhibit BCSCs. For this purpose, we
found that the geneUc knockdown of POLG1 and POLG2 genes in MCF-7 breast cancer cells
determines mitochondrial DNA depleUon, mitochondrial encoded protein reducUon,
depleted mitochondrial energy producUon, and decreased stemness properUes.
Furthermore, our study has been focused on finding a pharmacological approach to inhibit
mitochondrial DNA replicaUon using the polymerase gamma (POLG) genes as new
therapeuUc targets for breast cancer stem cells eradicaUon. To this end, we focused on the
nucleoside reverse trascriptase inhibitors (NRTIs) Alovudine and Zalcitabine (ddC),
originally developed for HIV (Human immunodeficiency virus) infecUon therapy, because
of their funcUon as POLG inhibitors, which is due to their high affinity for the polymerase
16
g. In MCF-7 cells, Alovudine and Zalcitabine (ddC) decreased the clonogenic potenUal,
reduced mitochondrial DNA encoded protein and decreased oxygen consumpUon.
Although there are conflicUng results in the literature, Mitochondrial DNA polymerase
gamma could be characterized as a potenUal mitochondrial target for drugs, such as
nucleoside analogs, for halUng BCSCs. Furthermore, we idenUfied the Tri-PhenylPhosphonium (TPP+
) derivaUve 4-CF3-TPP+
-DC, as a new mitochondrially- targeted inhibitor
of breast cancer stem cell propagaUon.

Citation

Chinigo, C. (2024). Role of Mitochondrial DNA Polymerase gamma (POLG) in Breast Cancer. (Thesis). University of Salford

• Thesis Type: Thesis
• Deposit Date: Mar 13, 2024
• Publicly Available Date: Mar 27, 2026
• Award Date: Mar 26, 2024