Understanding the Role of Autophagy in Breast Cancer.
Autophagy is a catabolic process in which unwanted and dysfunctional cytoplasmic components are engulfed and degraded through autophagosomes and lysosomes. Autophagy is an evolutionary conserved process for maintaining homeostasis in the cell under pressure and aid in cell survival. Although the mechanism of autophagy have not been completely elucidated, evidences show that it performs a dual role in breast cancer; maintaining homeostasis and preserving the activity of breast cancer stem cells (CSCs). It also plays a complex role in breast CSC therapy. Breast CSCs mainly have the ability of self-renewal, differentiate as well as begin and maintain tumor growth. They have an essential part in cancer recurrence and metastasis. (Mowers EE et al., 2017)
Breast cancer is the most typical and aggressive type of tumor affecting women. The standard characteristics of patients with breast cancer are that they have the receptors of estrogen (ER) and progesterone (PR) and respond to the hormone therapy. Basically, hormone therapy and radiotherapy have increased the survival rated in patients with breast cancer but triple negative breast cancer (TNBC) which is characterized by the presence of human epidermal growth factor receptor (HER), estrogen and progesterone receptors (ER & PR), is nonresponsive to these therapies. Therefore, there is a need for the development of new strategies that can target these cells. Recently, studies have proved that autophagy plays a critical role in life-threatening diseases including cancer. (Mohd Ishaq et al., 2020)
Autophagy is considered as a key factor in cell growth and hence, its inhibition can decrease the growth of tumor cells. Cancer associated fibroblasts (CAFs) promotes malignant cancer progression. As compared to normal fibroblasts, CAFs have higher conversion levels of Beclin1 and LC3-II/I protein. CAF autophagy can strengthen triple negative breast cancer (TNBC) cell proliferation. In addition to this, recent research shows that anticancer therapy may prompt autophagy affecting cancer cell proliferation. (Vessoni AT et al., 2013). Hence, the amalgamation of autophagy inhibition and chemotherapy may be an effective therapy for breast cancer. Chloroquine (CQ) which is an autophagy inhibitor removes CSCs through an epigenetic mechanism by fixing DNA methylation. Chloroquine leads to mitochondrial damage and simultaneously cell death in TNBC CSCs. (A. David et al., 2019)
The characteristics of cell death type I includes decrease in cell volume, damage of cellular cytoskeleton, fragmentation and condensation of nuclear content, and formation of apoptotic bodies which are disposed by phagocytes. There are two ways that mediate apoptosis: rectal and mitochondrial pathway. It has been seen that many types of cancer cells lack death-associated protein kinase (DAPK). (Laura Vera-Ramirez et al., 2018). Phosphorylated Beclin1 can promote the discharge of Beclin1 from Bcl-2 related proteins and induce autophagy. The protein separates by caspases, Bcl-2 which is a negative regulator of Beclin1. This protein can inhibit autophagy and hence enhance apoptosis. ATG5 is cleaved by calpains in order to produce an N-terminal ATG5 cleavage product, which is said to induce cytochrome c release from mitochondria. Cell survival and cell death both are complex processes therefore autophagy and apoptosis both play a significant role in it. Based on the researches, both autophagy and apoptosis share common factors. (Kumar D. et al., 2013)
Autophagy effectively decreases necrosis and inflammatory cell infiltration from the tumor sites by providing metabolic precursors. Based on this research, a complicated association between metastasis and autophagy has been established. Epithelial to mesenchymal transition (EMT) is important in spreading tumor. The two primary regulators, which are Snail and Slug, that can promote EMT by influencing the loss of epithelial (E)-cadherin-mediated cell-cell adhesion, are related to autophagy. Autophagy inadequacy has promoted EMT by sustaining Twist1. Recent autophagy and metastasis have been recognized as therapeutic methods. For example, the downregulation of macroautophagy related with ATG5 by chaperone-regulated autophagy was shown to promote breast cancer cell metastasis. (Han Q. et al., 2017)
Autophagy is very crucial in all stages of breast cancer. In a recent study, it was shown to reduce cancerous growth and decrease inflammation, and chromatin instability and tissue injury in the initial stages of cancer. In later stages, autophagy can also perform complex functions which are dependent on internal and external factors. One of the characteristics of cancer is proliferation which leads to metastasis and nutrient deficiency (A.V. Onorati et al., 2018). Autophagy tends to induce the metastatic process by maintaining cell survival, and enabling them to enter a dormant state if they could not contact with the extracellular matrix in the environment. Moreover, in transformed cancer cells, the inadequacy of autophagy can enable malignant tumor metastasis and neoplasia. However, it can also facilitate breast cancer progression, separation of genotoxic stress and genomic instability. (Mowers EE et al., 2017)
Autophagy promotes the anticancer response in breast cancer cells. It exerts effects on initiation, proliferation of cells and on the progression of tumors and CSCs. Hence, it is necessary to raise our knowledge regarding the inhibitors of autophagy. (Yanyan Han et al., 2018)
In conclusion, autophagy is a complex network of stress response. Its exact function in breast cancer remains uncertain but it sure affects developmental and metastatic stages of breast cancer. Autophagy seems to play a crucial role in breast cancer and its function in interlinked with other factors like metabolic reactions, tumor microenvironment (TME) and immunoreactions. (Mowers EE et al., 2017)
Ms. Snehal Kale, M.Sc (Biomedical Genetics), School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, India.
January 29, 2021
Dr. Arbab Khan, Ph.D (Scientific editor at Bio-Services). https://www.bio-services.org/dr-arbab-khan-ph-d/
- 1.Vessoni AT, Filippi-Chiela EC, Menck CF and Lenz G: Autophagy and genomic integrity. Cell Death Differ 20: 1444-1454, 2013.
- 2. Mowers EE, Shari MN and Macleod KF: Autophagy in cancer metastasis. Oncogene 36: 1619-1630, 2017.
- 3. Mohd Ishaq, Rani Ojha, Aditya P. Sharma, Shrawan K. Singh: Autophagy in cancer: Recent advances and future directions. Cancer Biology 66: 171-181, 2020
- 4. V. Onorati, M. Dyczynski, R. Ojha, R.K. Amaravadi, Targeting autophagy in cancer, Cancer 124,3307–3318. 2018.
- 5. Laura Vera-Ramirez, Suman K. Vodnala, Ryan Nini, Kent W. Hunter & Jeffrey E. Green: Autophagy promotes the survival of dormant breast cancer cells and metastatic tumour recurrence: Article No.- 1944, 2018.
- 6. David, D.A. Gewirtz, The challenge of developing autophagy inhibition as a therapeutic strategy, Cancer Res. 19, 5610–5614, 2019.
- 7. Han Q, Deng Y, Chen S, Chen R, Yang M, Zhang Z, Sun X, Wang W, He Y, Wang F, et al: Downregulation of ATG5- dependent macroautophagy by chaperone-mediated autophagy promotes breast cancer cell metastasis. Sci Rep 7: 4759, 2017.
- 8. Kumar D, Shankar S and Srivastava RK: Rottlerin-induced autophagy leads to the apoptosis in breast cancer stem cells: Molecular mechanisms. Mol Cancer 12: 171, 2013.
- 9. Yanyan Han, Shujun Fan, Tao Qin, Jinfeng Yang, Yan Sun, Ying Lu, Jun Mao, Lianhong Li: Role of autophagy in breast cancer and breast cancer stem cells. January 2018.