Impact of CASP3 Gene in Chemoresistance

Breast cancer (BC) is the most common malignant tumor in women and the biggest threat to the health of women worldwide. Breast cancer represents a significant global health challenge: it is the most commonly diagnosed cancer in the world with an estimated 2.26 million cases recorded in 2020. Breast cancer is rarely seen in males. The incidence of breast cancer rises rapidly over the years, ranking as the first common cancer among females worldwide, and thus posing a considerable threat to female health. Breast cancer is the leading cause of cancer mortality among females. Although historically considered to be a disease of largely developed countries, over half of breast cancer diagnoses and two-thirds of breast cancer related deaths occurred in the less developed regions of the world in 2020.Being a highly prevalent cancer type, breast cancer is observed in both developing and developed countries with different causes and factors of progression. Adopting new life styles, industrialization, globalization, increased life expectancy, pollution etc are the leading causes of cancer. According to 2018 statistics, every year around 1.2 million new cases of breast cancer were diagnosed. The GLOBACON report of 2018 concluded that breast cancer was the most frequently identified cancer type and leading cause of cancer related death in majority of countries. Major part of breast related cancer is linked with the expression of estrogen receptors and their treatment is related with the disease prognosis. The rate of breast cancer mortality can be reduced down to a limit by early diagnosis; timely treatment and management . The commonly used chemotherapeutic drugs include doxorubicin (DOX), paclitaxel and cyclophosphamide. However, the efficiency of chemotherapy is greatly limited by primary and acquired drug resistance . Chemotherapy is widely accepted as traditional treatment method in spite of the obstacle of chemotherapy resistance. The important mechanisms that may lead to drug resistance include alteration in expression of ABC transporters gene family, damage of topoisomerase enzyme, mutation in DNA repair genes, induced apoptosis by genetic imbalance and alteration in signalling pathways of NF alpha etc. All these worsen the condition of breast cancer making chemotherapy a failure in most cases. According to Yaghoubi et al., 2015, the cells which already acquired drug resistance show cross resistance to anti proliferative nature of anti-oestrogen drugs which have crucial role in breast cancer treatment .Caspase-3, a cysteine-aspartic acid protease, has recently attracted much attention . Caspase-3 is a protein (also called CPP32 or apopain), encoded by the CASP3 gene; which is located in the 4q34 with size 2635 bp. It mediates apoptosis in response to chemotherapy, but losing caspase 3 activity causes cell survival and induces drug resistance through apoptotic pathway in breast cancer .Caspase-3 has been identified as a key mediator of apoptosis, activated in apoptotic cells by both extrinsic (death ligands) and intrinsic (mitochondrial) pathways. It also has several nonapoptotic functions such as involving in tissue differentiation, regeneration, and neural development. Nonconforming activation of caspase-3 can lead to tumorigenesis instead of inducing the programmed cell death.Recent progress in caspase research indicates that caspases-3 is a prominent enzyme not only in apoptotic flux but also in nonapoptotic processes such as tissue differentiation, tissue regeneration, and neural development.