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Unveiling the vulnerabilities of synthetic lethality in triple-negative breast cancer

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Abstract

Triple-negative breast cancer (TNBC) is the most invasive molecular subtype of breast cancer (BC), accounting for about nearly 15% of all BC cases reported annually. The absence of the three major BC hormone receptors, Estrogen (ER), Progesterone (PR), and Human Epidermal Growth Factor 2 (HER2) receptor, accounts for the characteristic “Triple negative” phraseology. The absence of these marked receptors makes this cancer insensitive to classical endocrine therapeutic approaches. Hence, the available treatment options remain solemnly limited to only conventional realms of chemotherapy and radiation therapy. Moreover, these therapeutic regimes are often accompanied by numerous treatment side-effects that account for early distant metastasis, relapse, and shorter overall survival in TNBC patients. The rigorous ongoing research in the field of clinical oncology has identified certain gene-based selective tumor-targeting susceptibilities, which are known to account for the molecular fallacies and mutation-based genetic alterations that develop the progression of TNBC. One such promising approach is synthetic lethality, which identifies novel drug targets of cancer, from undruggable oncogenes or tumor-suppressor genes, which cannot be otherwise clasped by the conventional approaches of mutational analysis. Herein, a holistic scientific review is presented, to undermine the mechanisms of synthetic lethal (SL) interactions in TNBC, the epigenetic crosstalks encountered, the role of Poly (ADP-ribose) polymerase inhibitors (PARPi) in inducing SL interactions, and the limitations faced by the lethal interactors. Thus, the future predicament of synthetic lethal interactions in the advancement of modern translational TNBC research is assessed with specific emphasis on patient-specific personalized medicine.

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Abbreviations

ACS:

American cancer society

BC:

Breast cancer

BER:

Base excision repair

CDK:

Cyclin-dependent kinase

ChIP:

Chromatin immunoprecipitation sequencing

CRISPR:

Clustered regularly interspaced short palindromic repeats

CSC:

Cancer stem cells

DDFS:

Distant disease-free survival

DFS:

Disease-free survival

DDR:

DNA damage response

DSB:

Double-strand break

DSC:

Double-strand crosslink

EMA:

European medicines agency

EMT:

Epithelial–mesenchymal transformation

ER:

Estrogen receptor

gPALB2:

Germline PALB2

gRNA:

Guide RNA

HER2:

Human epidermal growth factor receptor 2

HMG:

Mobility group (protein)

HR:

Homologous recombination

HRR:

Homologous recombination repair

IDFS:

Invasive disease-free survival

lncRNA:

Long non-coding RNA

LOH:

Loss of heterozygosity

MDR:

Multidrug resistance

MHEJ:

Microhomology-mediated end joining

MRD:

Minimal residual disease

NGS:

Next-generation sequencing

NHEJ:

Non-homologous end joining

NLS:

Nuclear localizing sequence

OS:

Overall survival

ORR:

Overall response rate

PARPi:

Poly (ADP-ribose) polymerase inhibitor

PFS:

Progression-free survival

pi-RNA:

Piwi-interacting RNA

PR:

Progesterone receptor

RNAi:

RNA interference

SDL:

Synthetic dosage lethality

SR:

Serine and arginine-rich (proteins)

sgRNA:

Single-guide RNA

shRNA:

Short/small hairpin RNA

si-RNA:

Small interfering RNA

SL:

Synthetic lethal

sBRCA:

Somatic BRCA

SSB:

Single-strand break

TME:

Tumor microenvironment

TNBC:

Triple-negative breast cancer

TSG:

Tumor suppressor gene

WHO:

World Health Organization

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Acknowledgements

The authors sincerely thank the management of Bethune College, Vellore Institute of Technology, Vellore, and the Council of Scientific and Industrial Research (CSIR), New Delhi, for providing all the necessary amenities required for the development of this computational work.

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  1. Department of Botany, Bethune College, Kolkata, West Bengal, 700006, India

    Prarthana Chatterjee & Smita Ray

  2. School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India

    Rohit Karn & Arnold Emerson Isaac

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  1. Prarthana Chatterjee
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Chatterjee, P., Karn, R., Isaac, A.E. et al. Unveiling the vulnerabilities of synthetic lethality in triple-negative breast cancer. Clin Transl Oncol 25, 3057–3072 (2023). https://doi.org/10.1007/s12094-023-03191-9

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