Celina Garcia-Brinker

Introduction. This literature review focuses on breast cancer and more specifically how controlling/reducing cancer stem cells (CSC) can provide beneficial effects including limiting epithelial-mesenchymal-transition (EMT), which allows for metastasis, as well as increasing chemo-sensitivity ^1,5. Cancer stem cells are a critical component of tumor maintenance, especially for progression, invasion and metastasis ^1-3. Breast cancer is the second leading cause of death for women and the most common cancer diagnosed in women^1,8. For this aforementioned reason, it is important to identify ways to try and control the progression of the cancer. Current literature suggests that there are certain differentiating pathways that contribute to the production and maintenance of CSC^3,5,6. This literature research further analyzes a microRNA-34a as a potential inhibitor of notch1 signaling – a differentiation signaling pathway –  that can decrease CSC’s ability to induce EMT and chemoresistance^2,4,5. Methods. MCF-7, a breast cancer cell line, were used to determine the notch1 signaling and its correlation with microRNA-34a⁶. They were transfected with synthesized microRNA-34a⁶. A western blot was performed to analyze the presence of notch protein and microRNA-34a present in both control and transfected MCF-7 cells⁶. A migration and invasion assay were performed using a hematoxylin and eosin (H&E) stain⁶. A mammosphere formation assay was also performed to count the total spheres present with chemotherapy treatment of paclitaxel and microRNA-34a in MCF-7 breast cells⁶. Results. The western blot analysis demonstrated that MicroRNA-34a was found to have a negative correlation with Notch 1 signaling⁶. When microRNA-34a was introduced into the tumor, there was a decrease in tumor size⁶. H&E stains, showing markers for invasion and migration, resulted in a decrease in eosinophilia⁶. Lastly, there were less mammospheres present in the tumor when chemotherapy and microRNA-34a were used in conjunction⁶. Conclusion. In conclusion, the upregulation of microRNA-34a in tumor cells can downregulate notch signaling; thereby, decreasing the ability of CSC to aid in EMT. Limiting EMT has the potential to limit invasion and migration characteristics of the breast tumor, which were shown in the H&E stains⁶. This potential mechanism also has the ability to reduce tumor size by inhibiting the ability of the cancer stem cells to maintain the tumors growth^4,6,7.  Research also concluded a reduction of notch1 signaling, due to an upregulation of microRNA-34a, allowed for a more effective treatment with chemotherapy because of a decrease in CSC’s ability to support chemoresistance^4,6,7.

1. Byler S, Heerboth S, Leary M, Housman G, Moulton K, Sarkar S. Genetic and Epigenetic Aspects of Breast Cancer Progression and Therapy. Anticancer Research. 34.
2. Das V, Bhattacharya S, Chikkaputtaiah C, Hazra S, Pal M. The basics of epithelial–mesenchymal transition (EMT): A study from a structure, dynamics, and functional perspective. Journal of Cellular Physiology. 2019.
3. Heerboth S, Housman G, Leary M, et al. EMT and tumor metastasis. Clinical and Translational Medicine. 2015;4(1).
4. Imani S, Wei C, Cheng J, et al. MicroRNA-34a targets epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs) and inhibits breast cancer cell migration and invasion. Oncotarget. 2017;8(13).
5. Iqbal W, Alkarim S, Alhejin A, Mukhtar H, Saini KS. Targeting signal transduction pathways of cancer stem cells for therapeutic opportunities of metastasis. Oncotarget. 2016;7(46). doi:10.18632/oncotarget.10942.
6. Kang L, Mao J, Tao Y, et al. MicroRNA-34a suppresses the breast cancer stem cell-like characteristics by downregulating Notch1 pathway. Cancer Science. 2015;106(6):700-708. doi:10.1111/cas.12656.
7. Park EY, Chang E, Lee EJ, et al. Targeting of miR34a–NOTCH1 Axis Reduced Breast Cancer Stemness and Chemoresistance.
8. Winters S, Martin C, Murphy D, Shokar NK. Breast Cancer Epidemiology, Prevention, and Screening. Progress in Molecular Biology and Translations Science. 2017;151(1877):1877-1173