Underlying anti-cancer mechanisms of histone deacetylase (HDAC) inhibitors in tamoxifen-resistant breast cancer cells

Document Type : Original Article


1 Department of Breast Surgery, Baoding First Central Hospital, Baoding, Hebei, 071000, China

2 Chengde Medical College, Chengde, Hebei, China


Objective(s): Breast cancer is an important women’s malignancy with high cancer-related deaths worldwide. Drug resistance lowers the treatment efficacy in this malignancy. This study aimed to explore the underlying mechanisms of histone deacetylase (HDAC) inhibitor trichostatin A (TSA) to overcome resistance to tamoxifen in breast cancer cells.
Materials and Methods: Tamoxifen-resistance in MCF-7 breast cancer cells was simulated. MTT assay was used to detect the cytotoxic effects of HDAC inhibitor and PI3K inhibitor on the cancer cells. Trans-well assay was applied to evaluate the invasion and migration of the treated cancer cells. Flow cytometer assay was also applied to evaluate cell cycle phases in the treated cancer cells. Finally, expression of vascular endothelial growth factor (VEGF), E-cadherin, Vimentin, phosphorylated phosphatidylinositol kinase (p-PI3k), phosphorylated protein kinase B (p-AKT), and phosphorylated mammalian target protein of rapamycin (p-mTOR) was evaluated by western blotting.
Results: The obtained results indicated that HDAC inhibitor treatments significantly decreased viability, migration, and invasion in the cancer cells. Furthermore, the frequency of the treated cancer cells significantly increased in the S phase as well as significantly decreasing in the G2/M phase of the cell cycle. Moreover, HDAC inhibitor modified levels of VEGF, E-cadherin, Vimentin, p-PI3k, p-AKT, and p-mTOR proteins. However, HDAC inhibitor combined with PI3K inhibitor exerts more profound effects on the cancer cells as compared to HDAC inhibitor monotherapy.
Conclusion: HDAC inhibitors inhibited the survival of breast cancer drug-resistant cells, invasion, migration, and angiogenesis by inhibiting the PI3k/Akt/mTOR signaling pathway.


Main Subjects

1. Omene C, Ma L, Moore J, Ouyang H, Illa-Bochaca I, Chou W, et al. Aggressive mammary cancers lacking lymphocytic infiltration arise in irradiated mice and can be prevented by dietary intervention. Cancer Immunol Res 2020;8:217-229.
2. Zhou D, Ouyang Q, Liu L, Liu J, Tang Y, Xiao M, et al. Chemotherapy modulates endocrine therapy-related resistance mutations in metastatic breast cancer. Transl Oncol 2019; 12: 764-774.
3. Maroufi NF, Rashidi M, Vahedian V, Jahanbazi R, Mostafaei S, Akbarzadeh M, et al. Effect of Apatinib plus melatonin on vasculogenic mimicry formation by cancer stem cells from breast cancer cell line. Breast Cancer 2022; 29: 260-273.
4. Jahangiri B, Khalaj-Kondori M, Asadollahi E, Dizaj LP, Sadeghizadeh M. MSC-Derived exosomes suppress colorectal cancer cell proliferation and metastasis via miR-100/mTOR/miR-143 pathway. Int J Pharm 2022; 627: 122214.
5. Salek Farrokhi A, Mohammadlou M, Abdollahi M, Eslami M, Yousefi B. Histone deacetylase modifications by probiotics in colorectal cancer. J Gastrointest Cancer 2020; 51: 754-764.
6. Sun X, Luo S, Jiang C, Tang Y, Cao Z, Jia H, et al. Sodium butyrate reduces bovine mammary epithelial cell inflammatory responses induced by exogenous lipopolysaccharide, by inactivating NF-κB signaling. J Dairy Sci 2020; 103: 8388-8397.
7. Li Y, Seto E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb Perspect Med 2016; 6: a026831-26864.
8. Sun Y, Sun Y, Yue S, Wang Y, Lu F. Histone deacetylase inhibitors in cancer therapy. Curr Top Med Chem 2018;18:2420-2428.
9. Libby EN, Becker PS, Burwick N, Green DJ, Holmberg L, Bensinger WI. Panobinostat: A review of trial results and future prospects in multiple myeloma. Expert Rev Hematol 2015; 8: 9-18.
10. Chavoshi H, Poormolaie N, Vahedian V, Kazemzadeh H, Mir A, Nejabati HR, et al. Vascular mimicry: A potential therapeutic target in breast cancer. Pathol Res Pract 2022; 234: 153922.
11. Taefehshokr S, Taefehshokr N, Derakhshani A, Baghbanzadeh A, Astamal RV, Safaei S, et al. The regulatory role of pivotal microRNAs in the AKT signaling pathway in breast cancer. Curr Mol Med 2022; 22: 263-273.
12. Ghahremani Dehbokri S, Alizadeh N, Isazadeh A, Baghbanzadeh A, Abbaspour-Ravasjani S, Hajiasgharzadeh K, et al. CTLA-4: As an immunosuppressive immune checkpoint in breast cancer. Curr Mol Med 2023; 23: 521-526.
13. Soheilyfar S, Velashjerdi Z, Hajizadeh YS, Maroufi NF, Amini Z, Khorrami A, et al. In vivo and in vitro impact of miR-31 and miR-143 on the suppression of metastasis and invasion in breast cancer. J BUON 2018; 23: 1290-1296.
14. Tecalco-Cruz AC, Ramírez-Jarquín JO, Cruz-Ramos E. Estrogen receptor alpha and its ubiquitination in breast cancer cells. Curr Drug Targets 2019;20:690-704.
15. Hieu DT, Anh DT, Hai PT, Thuan NT, Huong LT, Park EJ, et al. Quinazolin‐4 (3H)‐one‐Based hydroxamic acids: Design, synthesis and evaluation of histone deacetylase inhibitory effects and cytotoxicity. Chem Biodivers 2019;16:e1800502.
16. Zhang XQ, Yao C, Bian WH, Chen X, Xue JX, Zhu ZY, et al. Effects of Astragaloside IV on treatment of breast cancer cells execute possibly through regulation of Nrf2 via PI3K/AKT/mTOR signaling pathway. Food Sci Nutr 2019; 7: 3403-3413.
17. Bakhshaiesh TO, Armat M, Shanehbandi D, Sharifi S, Baradaran B, Hejazi MS, et al. Arsenic trioxide promotes paclitaxel cytotoxicity in resistant breast cancer cells. Asian Pac J Cancer Prev 2015; 16: 5191-5197.
18. Jin XH, Jia YS, Shi YH, Li QY, Bao SQ, Lu WP, et al. ACT001 can prevent and reverse tamoxifen resistance in human breast cancer cell lines by inhibiting NF‐κB activation. J Cell Biochem 2019; 120: 1386-1397.
19. Han M, Wang Y, Guo G, Li L, Dou D, Ge X, et al. MicroRNA‐30d mediated breast cancer invasion, migration, and EMT by targeting KLF11 and activating STAT3 pathway. J Cell Biochem 2018;119:8138-8145.
20. Li H, Zhao B, Liu Y, Deng W, Zhang Y. Angiogenesis in residual cancer and roles of HIF-1α, VEGF, and MMP-9 in the development of residual cancer after radiofrequency ablation and surgical resection in rabbits with liver cancer. Folia Morphol 2020; 79: 71-78.
21. Huang J, Liu C, Duan S, Lin J, Luo Y, Tao S, et al. Gigantol inhibits proliferation and enhances DDP-induced apoptosis in breast-cancer cells by downregulating the PI3K/Akt/mTOR signaling pathway. Life Sci 2021; 274: 119354.
22. Maric G, Annis MG, MacDonald PA, Russo C, Perkins D, Siwak DR, et al. GPNMB augments Wnt-1 mediated breast tumor initiation and growth by enhancing PI3K/AKT/mTOR pathway signaling and β-catenin activity. Oncogene 2019; 38: 5294-5307.
23. Wei J, Zhang X, Pan H, He S, Yuan B, Liu Q, et al. Eupafolin inhibits breast cancer cell proliferation and induces apoptosis by inhibiting the PI3K/Akt/mTOR pathway. Oncol Lett 2021; 21: 1-9.