DNA Repair and Therapeutic Strategies in Cancer Stem Cells.

First-line cancer treatments successfully eradicate the differentiated tumour mass but are comparatively ineffective against cancer stem cells (CSCs), a self-renewing subpopulation thought to be responsible for tumour initiation, metastasis, heterogeneity, and recurrence. CSCs are thus presented as the principal target for elimination during cancer treatment. However, CSCs are challenging to drug target because of numerous intrinsic and extrinsic mechanisms of drug resistance. One such mechanism that remains relatively understudied is the DNA damage response (DDR). CSCs are presumed to possess properties that enable enhanced DNA repair efficiency relative to their highly proliferative bulk progeny, facilitating improved repair of double-strand breaks induced by radiotherapy and most chemotherapeutics. This can occur through multiple mechanisms, including increased expression and splicing fidelity of DNA repair genes, robust activation of cell cycle checkpoints, and elevated homologous recombination-mediated DNA repair. Herein, we summarise the current knowledge concerning improved genome integrity in non-transformed stem cells and CSCs, discuss therapeutic opportunities within the DDR for re-sensitising CSCs to genotoxic stressors, and consider the challenges posed regarding unbiased identification of novel DDR-directed strategies in CSCs. A better understanding of the DDR mediating chemo/radioresistance mechanisms in CSCs could lead to novel therapeutic approaches, thereby enhancing treatment efficacy in cancer patients.

MYBL2 amplification in breast cancer: Molecular mechanisms and therapeutic potential.

The MYBL2 gene, also known as B-MYB, is essential to regulate vital cellular processes including cell proliferation, differentiation and DNA repair. Changes in these pathways can facilitate cancer development and as such targeting these processes represent an effective method to treat multiple cancer types. Alterations in gene expression have been identified in cancer cells including changes in MYBL2, which appears to be of particular significance in breast cancer (BC) patients. Upregulation of MYBL2 in BC can occur via multiple mechanisms, including changes in regulation by micro RNAs, amplification of the 20q13 gene coding region and single nucleotide polymorphisms in the MYBL2 gene itself or associated genes. Evidence from multiple studies suggests MYBL2 expression could be used as a biomarker for disease severity in BC patients, which could identify those who require a more targeted treatment approach to prevent disease recurrence. In fact, high MYBL2 expression correlates with BC metastasis, worse relapse free survival and shorter overall survival, providing strong evidence that upregulation of MYBL2 functions contributes to more aggressive disease. This review summarises the significance of amplified MYBL2 expression to the development and pathogenesis of BC and suggests ways to target this multifunctional protein as an effective treatment to prevent disease recurrence.