Affiliation:
1. Cairo University Faculty of Pharmacy
2. Future University in Egypt
3. National Cancer Institute Cairo University
Abstract
Abstract
Androgen receptor (AR) and its splicing variant 7 (ARv7) play vital roles in the pathobiology of breast cancer (BC) but their role in the estrogen receptor-positive (ER+) type is controversial, hence, we studied the influence of the blockers of AR (Enzalutamide) and ARv7 (EPI-001) on tumorigenesis processes using T47D, an ER+ BC cell line. We showed that although both inhibitors failed to reduce cell growth and affect AR content, only Enzalutamide reduced the ARv7. Mechanistically, the drugs successfully arrested the cell cycle at S-phase and downregulated the protein expression of cyclins A, E, & C. Additionally, they inhibited the cell proliferation stimulator nuclear factor kappa B (NF-ĸB), whereas only EPI-001 reduced the cell regulatory marker c-Myc. They also opposed the endothelial-to-mesenchymal transition (EMT) process, by boosting the epithelial marker E-cadherin and reducing the protein expression of the mesenchymal marker fibronectin. Their anti-metastatic potential was evidenced by the hindrance of cell migration using the wound healing assay and further confirmed by the downregulation of metalloproteinase (MMP) 2 and 9 protein expression, and protein content of Rho kinase (ROCK)1 and 2. Besides, by downregulating the protein expression of vascular endothelial growth factor (VEGF) the drugs point to their anti-angiogenic aptitude. In conclusion, this in-vitro study is the first to prove the importance of blocking AR/ARv7 using Enzalutamide and EPI-001 in decreasing cancer cell survival, EMT, and metastasis in ER+ BC cells, findings that still need further studies to unveil the role of these inhibitors in BC.
Publisher
Research Square Platform LLC