Tocopherols Inhibit Estrogen-induced Cancer Stemness and OCT4 Signaling in Breast Cancer

Overview

Journal Carcinogenesis

Specialty Oncology

Date 2018 May 31

PMID 29846560

Citations 13

Authors

Min Ji Bak

Philip Furmanski

Naing Lin Shan

Hong Jin Lee

Cheng Bao

Yong Lin

Weichung Joe Shih

Chung S Yang

Nanjoo Suh

Affiliations

Soon will be listed here.

Abstract

Estrogen plays an important role in breast cancer development. While the mechanism of the estrogen effects is not fully elucidated, one possible route is by increasing the stem cell-like properties in the tumors. Tocopherols are known to reduce breast cancer development and progression. The aim of the present study is to investigate the effects of tocopherols on the regulation of breast cancer stemness mediated by estrogen. To determine the effects of tocopherols on estrogen-influenced breast cancer stem cells, the MCF-7 tumorsphere culture system, which enriches for mammary progenitor cells and putative breast cancer stem cells, was utilized. Treatment with estrogen resulted in an increase in the CD44+/CD24- subpopulation and aldehyde dehydrogenase activity in tumorspheres as well as the number and size of tumorspheres. Tocopherols inhibited the estrogen-induced expansion of the breast cancer stem population. Tocopherols decreased the levels of stem cell markers, including octamer-binding transcription factor 4 (OCT4), CD44 and SOX-2, as well as estrogen-related markers, such as trefoil factor (TFF)/pS2, cathepsin D, progesterone receptor and SERPINA1, in estrogen-stimulated tumorspheres. Overexpression of OCT4 increased CD44 and sex-determining region Y-box-2 levels and significantly increased cell invasion and expression of the invasion markers, matrix metalloproteinases, tissue inhibitors of metalloproteinase and urokinase plasminogen activator, and tocopherols inhibited these OCT4-mediated effects. These results suggest a potential inhibitory mechanism of tocopherols in estrogen-induced stemness and cell invasion in breast cancer.

Citing Articles

Antiproliferative Role of Natural and Semi-Synthetic Tocopherols on Colorectal Cancer Cells Overexpressing the Estrogen Receptor β.

Falsetti I, Palmini G, Zonefrati R, Vasa K, Donati S, Aurilia C Int J Mol Sci. 2025; 26(5).

PMID: 40076925 PMC: 11900421. DOI: 10.3390/ijms26052305.

Exploring the potential of tocopherols: mechanisms of action and perspectives in the prevention and treatment of breast cancer.

Nava-Tapia D, Roman-Justo N, Cuenca-Rojo A, Guerrero-Rivera L, Patron-Guerrero A, Poblete-Cruz R Med Oncol. 2024; 41(9):208.

PMID: 39060448 DOI: 10.1007/s12032-024-02454-x.

Identification of AP002498.1 and LINC01871 as prognostic biomarkers and therapeutic targets for distant metastasis of colorectal adenocarcinoma.

Wu N, Chen J, Lin T, Zhong Z, Li M, Yu Y Cancer Med. 2023; 13(1):e6823.

PMID: 38083905 PMC: 10807603. DOI: 10.1002/cam4.6823.

Advances in Biomarkers and Endogenous Regulation of Breast Cancer Stem Cells.

Chen W, Zhang L, Liu S, Chen C Cells. 2022; 11(19).

PMID: 36230903 PMC: 9562239. DOI: 10.3390/cells11192941.

DNMT3A//Rac1 Is an Effector Pathway for to Drive Stem-Cell-like and Invasive Behaviors of Advanced Bladder Cancer Cells.

Xu J, Yang R, Li J, Wang L, Cohen M, Simeone D Cancers (Basel). 2022; 14(17).

PMID: 36077697 PMC: 9454896. DOI: 10.3390/cancers14174159.

References

Louderbough J, Schroeder J . Understanding the dual nature of CD44 in breast cancer progression. Mol Cancer Res. 2011; 9(12):1573-86. DOI: 10.1158/1541-7786.MCR-11-0156. View

Liu T, Wu Y, Guo X, Hui J, Lee E, Lim B . Effects of ectopic Nanog and Oct4 overexpression on mesenchymal stem cells. Stem Cells Dev. 2008; 18(7):1013-22. PMC: 3190294. DOI: 10.1089/scd.2008.0335. View

Fan P, Agboke F, Cunliffe H, Ramos P, Jordan V . A molecular model for the mechanism of acquired tamoxifen resistance in breast cancer. Eur J Cancer. 2014; 50(16):2866-76. PMC: 4194144. DOI: 10.1016/j.ejca.2014.08.011. View

Buganim Y, Faddah D, Jaenisch R . Mechanisms and models of somatic cell reprogramming. Nat Rev Genet. 2013; 14(6):427-39. PMC: 4060150. DOI: 10.1038/nrg3473. View

Bourboulia D, Stetler-Stevenson W . Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Semin Cancer Biol. 2010; 20(3):161-8. PMC: 2941566. DOI: 10.1016/j.semcancer.2010.05.002. View

Fillmore C, Gupta P, Rudnick J, Caballero S, Keller P, Lander E . Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. Proc Natl Acad Sci U S A. 2010; 107(50):21737-42. PMC: 3003123. DOI: 10.1073/pnas.1007863107. View

Gaziano J, Glynn R, Christen W, Kurth T, Belanger C, MacFadyen J . Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. JAMA. 2008; 301(1):52-62. PMC: 2774210. DOI: 10.1001/jama.2008.862. View

Moirangthem A, Bondhopadhyay B, Mukherjee M, Bandyopadhyay A, Mukherjee N, Konar K . Simultaneous knockdown of uPA and MMP9 can reduce breast cancer progression by increasing cell-cell adhesion and modulating EMT genes. Sci Rep. 2016; 6:21903. PMC: 4764826. DOI: 10.1038/srep21903. View

Pan G, Chang Z, Scholer H, Pei D . Stem cell pluripotency and transcription factor Oct4. Cell Res. 2003; 12(5-6):321-9. DOI: 10.1038/sj.cr.7290134. View

10.

Lin H, Sun L, Han W, He T, Xu X, Cheng K . Knockdown of OCT4 suppresses the growth and invasion of pancreatic cancer cells through inhibition of the AKT pathway. Mol Med Rep. 2014; 10(3):1335-42. PMC: 4121418. DOI: 10.3892/mmr.2014.2367. View

11.

Simoes B, Vivanco M . Cancer stem cells in the human mammary gland and regulation of their differentiation by estrogen. Future Oncol. 2011; 7(8):995-1006. DOI: 10.2217/fon.11.80. View

12.

Godar S, Ince T, Bell G, Feldser D, Liu Donaher J, Bergh J . Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell. 2008; 134(1):62-73. PMC: 3222460. DOI: 10.1016/j.cell.2008.06.006. View

13.

Leis O, Eguiara A, Lopez-Arribillaga E, Alberdi M, Hernandez-Garcia S, Elorriaga K . Sox2 expression in breast tumours and activation in breast cancer stem cells. Oncogene. 2011; 31(11):1354-65. DOI: 10.1038/onc.2011.338. View

14.

Lee H, Liu H, Goodman C, Ji Y, Maehr H, Uskokovic M . Gene expression profiling changes induced by a novel Gemini Vitamin D derivative during the progression of breast cancer. Biochem Pharmacol. 2006; 72(3):332-43. DOI: 10.1016/j.bcp.2006.04.030. View

15.

Das Gupta S, So J, Wall B, Wahler J, Smolarek A, Sae-Tan S . Tocopherols inhibit oxidative and nitrosative stress in estrogen-induced early mammary hyperplasia in ACI rats. Mol Carcinog. 2014; 54(9):916-25. PMC: 4492905. DOI: 10.1002/mc.22164. View

16.

Kessenbrock K, Plaks V, Werb Z . Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010; 141(1):52-67. PMC: 2862057. DOI: 10.1016/j.cell.2010.03.015. View

17.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

18.

Hu J, Guo H, Li H, Liu Y, Liu J, Chen L . MiR-145 regulates epithelial to mesenchymal transition of breast cancer cells by targeting Oct4. PLoS One. 2012; 7(9):e45965. PMC: 3458807. DOI: 10.1371/journal.pone.0045965. View

19.

Dai X, Ge J, Wang X, Qian X, Zhang C, Li X . OCT4 regulates epithelial-mesenchymal transition and its knockdown inhibits colorectal cancer cell migration and invasion. Oncol Rep. 2012; 29(1):155-60. DOI: 10.3892/or.2012.2086. View

20.

Guan F, Li G, Liu A, Lee M, Yang Z, Chen Y . δ- and γ-tocopherols, but not α-tocopherol, inhibit colon carcinogenesis in azoxymethane-treated F344 rats. Cancer Prev Res (Phila). 2012; 5(4):644-54. PMC: 3324634. DOI: 10.1158/1940-6207.CAPR-11-0521. View