Circulating Tumor Cells in Breast Cancer Patients: A Balancing Act between Stemness, EMT Features and DNA Damage Responses
Abstract
:Simple Summary
Abstract
1. DNA Repair Defects Play Key Roles during the Development of Breast Cancer
2. Dynamic Changes in DNA Damage Responses Are Intricately Linked with EMT and Stemness Features during Breast Cancer Progression
2.1. EMT and DNA Repair
2.1.1. Signaling from the Cellular Surface
2.1.2. Crosstalk between Nuclear DNA Damage Response Components and EMT
2.2. Stemness and DNA Repair
3. Dynamic Changes in the Regulatory Network of Stemness, EMT Features and DNA Damage Responses of CTCs
3.1. Plasticity Causes Stress in CTCs
3.1.1. Interplay between Stemness, EMT and DNA Damage Response Pathways in CTCs
3.1.2. Sources of DNA Damage in CTCs
3.2. Evidence for CTC-Specific DNA Damage Responses and Their Manifestation at the Genomic Level in Breast Cancer Patients
3.2.1. Accumulation of Genomic Instabilities in CTCs from Breast Cancer Patients
3.2.2. CTC-Specific DNA Damage Responses of Breast Cancer Patients
4. Conclusions and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Effector/Effector Group | Target/Group of Targets | References |
---|---|---|
RTK | SLUG/SNAIL/TWIST1/ZEB1 | [34,35] |
NOTCH | SLUG/SNAIL/TWIST1/ZEB1 | [36] |
TGFß | BRCA1/FANCD2 | [37] |
TGFß | p53 | [38] |
TGFß | ATM/ATR | [35,39] |
TGFß | PARP3 | [40] |
TGFß | SLUG/SNAIL/TWIST1/ZEB1 | [41] |
SLUG/SNAIL/TWIST1/ZEB1 | TGFß | [34] |
E-Cadherin | TGFß | [42] |
SLUG/SNAIL/TWIST1/ZEB1 | E-Cadherin | [34] |
Vimentin | TGFß | [42] |
SLUG/SNAIL/TWIST1/ZEB1 | Vimentin | [43,44,45] |
SLUG/SNAIL/TWIST1/ZEB1 | polymerase θ | [46] |
BRCA1, FANCD2 | SLUG, SNAIL, TWIST1, ZEB1 | [47] |
BRCA1, FANCD2 | NOTCH | [48] |
SLUG/SNAIL/TWIST1/ZEB1 | BRCA1/FANCD2 | [49] |
RAP80 | SLUG/SNAIL/TWIST1/ZEB1 | [50,51] |
p53 | SLUG/SNAIL/TWIST1/ZEB1 | [52,53,54] |
SLUG, SNAIL, TWIST1, ZEB1 | p53 | [34,55,56] |
H2A.X | SLUG/SNAIL/TWIST1/ZEB1 | [57] |
RNF8 | SLUG/SNAIL/TWIST1/ZEB1 | [58] |
ATM/ATR | SLUG/SNAIL/TWIST1/ZEB1 | [34,41,59,60] |
SLUG/SNAIL/TWIST1/ZEB1 | ATM/ATR | [45,59,60] |
SLUG/SNAIL/TWIST1/ZEB1 | CHK1 | [34,59] |
PARP1 | SLUG/SNAIL/TWIST1/ZEB1 | [61] |
PARP3 | SLUG/SNAIL/TWIST1/ZEB1 | [40] |
Effect in CTCs | Observations | References |
---|---|---|
CNAs in primary BC correlate with CTC numbers | Copy number alterations (CNAs) in BC specimen of CTC-positive cases. | [191] |
CNAs rise with invasiveness | CNAs differ between CTCs from individual patients but not between CTCs from same patient. CNA numbers increase from patients with ductal carcinoma in situ (DCIS) to patients with invasive ductal carcinoma. | [2] |
Clonality of CTCs in MBC patients | NGS reveals high genomic clonality in CTCs from BC patients with brain metastases. | [158] |
HER2amplification acquired | Fluorescence in situ hybridization (FISH)-based detection of HER2 amplification provides evidence for acquisition in 37.5% of BC patients during progression and/or treatment. | [203] |
Microevolution of genomic rearrangements | Genomic disparity between primary BC and single CTCs detected by NGS; driver mutation-specific rise of CNAs. | [139,204] |
ESR1mutations acquired | Activating ESR1 mutations in CTCs from MBC patients after endocrine therapy; 85% concordance between key mutations and CNAs in CTCs and metastases. | [161] |
Increased oxidative stress | Intracellular ROS is elevated and counterbalanced by endogenous antioxidants in CTCs but not primary BC or MBC, which prevents apoptosis and permits metastasis. | [149,167] |
Potentiated DNA repair confers chemoresistance | γH2AX-marked basal DNA damage is elevated in CTCs versus attached BC cells and partially activates DNA damage responses. Comet assay- and γH2AX-marked DNA damage induced by cytostatics (Epirubicin, Cisplatin) is repaired faster in CTCs vs. attached BC cells irrespective of BC stemness. | [149] |
γH2AX monitors response to DNA damaging drugs | γH2AX signals accumulate in CTCs from BC and other patients after combined cyclophosphamide and PARP inhibitor treatment (Phase I). | [145,147] |
ERCC1expression before and after chemotherapy | ERCC1 mRNA expression analyzed by multiplex RT-PCR of separated CTCs shows expression in 60–70% of patients before and after neoadjuvant therapy. | [205] |
CNAs coupled with DNA repair gene alterations in CTC line | ER+ CTC line from MBC patient with wide spectrum of CNAs carries pathogenic TP53 mutation and predicted deleterious change in ATM. | [155] |
53BP1 associates with chemotherapy response | 53BP1 accumulates in CTCs from MBC patients with hormone receptor-positive metastases and in Eribulin-responsive patients. | [111] |
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Heitmeir, B.; Deniz, M.; Janni, W.; Rack, B.; Schochter, F.; Wiesmüller, L. Circulating Tumor Cells in Breast Cancer Patients: A Balancing Act between Stemness, EMT Features and DNA Damage Responses. Cancers 2022, 14, 997. https://doi.org/10.3390/cancers14040997
Heitmeir B, Deniz M, Janni W, Rack B, Schochter F, Wiesmüller L. Circulating Tumor Cells in Breast Cancer Patients: A Balancing Act between Stemness, EMT Features and DNA Damage Responses. Cancers. 2022; 14(4):997. https://doi.org/10.3390/cancers14040997
Chicago/Turabian StyleHeitmeir, Benedikt, Miriam Deniz, Wolfgang Janni, Brigitte Rack, Fabienne Schochter, and Lisa Wiesmüller. 2022. "Circulating Tumor Cells in Breast Cancer Patients: A Balancing Act between Stemness, EMT Features and DNA Damage Responses" Cancers 14, no. 4: 997. https://doi.org/10.3390/cancers14040997