Theranostic Interpolation of Genomic Instability in Breast Cancer

Abstract

Breast cancer is a diverse disease caused by mutations in multiple genes accompanying epigenetic aberrations of hazardous genes and protein pathways, which distress tumor-suppressor genes and the expression of oncogenes. Alteration in any of the several physiological mechanisms such as cell cycle checkpoints, DNA repair machinery, mitotic checkpoints, and telomere maintenance results in genomic instability. Theranostic has the potential to foretell and estimate therapy response, contributing a valuable opportunity to modify the ongoing treatments and has developed new treatment strategies in a personalized manner. "Omics" technologies play a key role while studying genomic instability in breast cancer, and broadly include various aspects of proteomics, genomics, metabolomics, and tumor grading. Certain computational techniques have been designed to facilitate the early diagnosis of cancer and predict disease-specific therapies, which can produce many effective results. Several diverse tools are used to investigate genomic instability and underlying mechanisms. The current review aimed to explore the genomic landscape, tumor heterogeneity, and possible mechanisms of genomic instability involved in initiating breast cancer. We also discuss the implications of computational biology regarding mutational and pathway analyses, identification of prognostic markers, and the development of strategies for precision medicine. We also review different technologies required for the investigation of genomic instability in breast cancer cells, including recent therapeutic and preventive advances in breast cancer.

Keywords: DNA repair pathways; PARP inhibitor; breast cancer; genomic instability.

Figure 1

Schematic representation of genomic instability in breast cancer. In humans, inherited mutations in ATM, P53, CHK1, CHK2, and BRCA1/BRCA2 genes, which are DNA damage checkpoints, are associated with predisposition to malignancy. Primarily, the exact etiology of breast cancer is not clear, but various estimated factors, including heritable, endogenous, and exogenous, may cause DNA damage. Initiation of checkpoint response requires ATM or ATR kinase, depending upon the type of DNA damage. In response to DNA damage, ATM or ATR phosphorylate different substrates such as BRCA1, P53, CHK1, and CHK2. The caretaker tumor-suppressor genes BRCA1 and BRCA2 maintain the integrity of the genome by fixing errors mainly related to DNA double-strand breaks and replication forks. Breast cancer cells cannot repair the DNA strand breaks due to mutations in BRCA1 or BRCA2, which may result in accumulation of mutations that are responsible for triggering proliferation and metastasis. On the other hand, in response to DNA damage, BRCA1-mutated cells have a defective checkpoint function in the G1/S phase of the cell cycle, as BRCA1 also plays an important role in mediating cell cycle arrest. In DNA damage response, BRCA1 acting as a scaffold protein facilitates p53 phosphorylation by ATM, which leads to p53-induced p21 induction and mediates G1/S arrest. Primarily, this will result in defective DNA repair and chromosome instability, which further leads to acquiring genomic instability and malignant features. In breast cancer cells, germline or somatic mutation, copy number aberration, and epigenetic control alteration have been shown to affect several genes that are responsible for maintaining genomic stability in normal conditions. Loss of key DNA damage repair genes including BRCA1, BRCA2, RAD52, PALB2, BR1P; and genome caretaker genes such as ATM, CHEK2, and TP53 are highly associated with increased risk of breast cancer development. PI3-K/Akt, the extracellular signaling pathway, is crucial for the control of cell growth and is normally regulated by several extracellular signaling proteins, including insulin and insulin-like growth factors. In cancer cells, this pathway is abnormally activated by mutation in PTEN, and cancer cells can grow in the absence of such a signal, so this abnormal activation of Akt is central to the dysregulated growth process. The most common mutation of the tumor-suppressor gene in breast cancer is the loss of PTEN phosphatase, the normal function of which is to limit Akt activation by dephosphorylating PI3K. The tumor suppressor PTEN is an important modulator of chk1 function. Akt activation in response to PTEN loss phosphorylates CHK1 and leads to its monoubiquitination and sequestration from the nucleus. Outside the nucleus, phosphorylated CHK1 is unable to respond to its activating substrate, AKT/ATM, and there will be no phosphorylation of its substrate, including CDC25. CDC25A is the major substrate of chk1, which is overexpressed in breast cancer cells. In breast cancer, CDC25A overexpression leads to activation of the cyclin E/cdk complex, and has shown to play a very vital role in the unscheduled firing of origins of replication and induction of chromosome instability. So, reduced PTEN leads to increased Akt activation and increased cytoplasmic chk1 phosphorylation, thereby inhibiting its checkpoint function. A reduced amount of chk1 function is predisposed to genomic instability, and contributes to the development of breast cancer. In addition, Akt activation inhibits cyclin/CDK complex inhibitors, including p21, p27, and CDC25, which stimulate cell cycle arrest in response to activation of checkpoints. Moreover, activation of Akt phosphorylates and activating MDM2 stimulate the destruction of p53. In p53-deficient cells, the blockage of cdk2/cyclin E by p21 is not functional, thus hyperamplification of the centrosome may occur, which is the prerequisite for mitotic catastrophe.