Circulating Tumor Cells in Breast Cancer Patients: A Balancing Act between Stemness, EMT Features and DNA Damage Responses

Abstract

Circulating tumor cells (CTCs) traverse vessels to travel from the primary tumor to distant organs where they adhere, transmigrate, and seed metastases. To cope with these challenges, CTCs have reached maximal flexibility to change their differentiation status, morphology, migratory capacity, and their responses to genotoxic stress caused by metabolic changes, hormones, the inflammatory environment, or cytostatic treatment. A significant percentage of breast cancer cells are defective in homologous recombination repair and other mechanisms that protect the integrity of the replication fork. To prevent cell death caused by broken forks, alternative, mutagenic repair, and bypass pathways are engaged but these increase genomic instability. CTCs, arising from such breast tumors, are endowed with an even larger toolbox of escape mechanisms that can be switched on and off at different stages during their journey according to the stress stimulus. Accumulating evidence suggests that DNA damage responses, DNA repair, and replication are integral parts of a regulatory network orchestrating the plasticity of stemness features and transitions between epithelial and mesenchymal states in CTCs. This review summarizes the published information on these regulatory circuits of relevance for the design of biomarkers reflecting CTC functions in real-time to monitor therapeutic responses and detect evolving chemoresistance mechanisms.

PSME2 offers value as a biomarker of M1 macrophage infiltration in pan-cancer and inhibits osteosarcoma malignant phenotypes

“…The DNA damage response is a complex series of mechanisms responsible for maintaining the stability and integrity of the genome by detecting and eliminating abnormal sequences and structures within chromosomes 48 . Tumor cells develop mechanisms that enable them to evade certain therapeutic strategies by co-opting the MMR 49 and HRR 50 mechanisms, endowing these tumor cells with stem-like self-maintenance abilities 51 . As such, the associations between PSME2 expression levels and MMR-associated genes, HRR signatures, and stemness were next evaluated.…”

DNA‐PKcs/AKT1 inhibits epithelial–mesenchymal transition during radiation‐induced pulmonary fibrosis by inducing ubiquitination and degradation of Twist1

“…41 Furthermore, studies have suggested that DSB repair may be involved in fibrosis. 42,43 EMTassociated transcription factors may also regulate DSB repair, [44][45][46][47][48] indicating that there may be crosstalk between DSB repair and EMT, and the role of DNA-PKcs-mediated regulation of DSB repair and senescence in alveolar epithelial cells in RIPF needs to be further elucidated in the future.…”

Canonical and non-canonical functions of p53 isoforms: potentiating the complexity of tumor development and therapy resistance

“…Independently of the precise mechanism affecting such non-canonical function of p53α, both fork stalling and dysregulated DDT pathway usage are known to cause genomic instability and thereby tumorigenesis [ 89 ]. Moreover, loss of fork protection and resulting DNA damage are known to be sufficient to induce EMT genes and thereby invasiveness and metastasis [ 157 ].…”