D/L-Homocysteine May Suppress Proliferative Properties of Tamoxifen-resistant MCF-7/TAMR-1 Breast Cancer Cells through Modulation of ER Stress

Abstract

Tamoxifen is an important treatment approach that is frequently used in the treatment of breast cancer, but its usage is limited due to changes in receptor expression profiles of breast cancer cells. Although tamoxifen has an intense clinical application area, 20-30% of breast cancer patients develop resistance to tamoxifen de novo or after treatment for various reasons. Breast cancer is the second cause of cancer-related death among women worldwide, and many people die from breast cancer each year. For this reason, many studies are continuing to increase the sensitivity of breast cancer cells to tamoxifen. Recent studies have pointed out that mechanisms related to endoplasmic reticulum (ER) stress are important key regulators of breast cancer progression and acquired drug resistance. Thus, agents that modulate ER stress are intensively investigated for new treatment approaches to be developed for cancer. In our studies, combined application of D/L-homocysteine with tamoxifen improves tamoxifen sensitivity of MCF-7/TAMR-1 cells, which well-mimic the development of tamoxifen resistance in vitro by ER stress modulation. Our findings suggest that combined treatment of new molecules that can affect the processes associated with ER stress, with tamoxifen, might be promising alternative approaches to be applied against tamoxifen resistance in breast cancer.

Keywords

• ER stress
• MCF-7/TAMR-1
• Breast Cancer
• Tamoxifen

D/L-Homosistein Tamoksifene Dirençli MCF-7/TAMR-1 Meme Kanseri Hücrelerinin Proliferatif Özelliklerini ER Stresi Aracılı Olarak Baskılayabilir

Abstract

Tamoksifen meme kanseri tedavisinde sıklıkla kullanılan ancak reseptör ifade profillerindeki değişimlere bağlı olarak kullanımı sınırlanan önemli bir tedavi yaklaşımıdır. Her ne kadar tamoksifen klinikte yoğun bir uygulama alanına sahip olsa da meme kanseri hastalarının %20-30'u çeşitli nedenlerle de novo veya tedavi sonrasında tamoksifene karşı direnç geliştirmektedir. Meme kanseri, dünya genelinde kadınlar arasında kansere bağlı ölümlerin ikinci nedenidir ve her yıl birçok kişi meme kanseri nedeniyle yaşamını yitirmektedir. Bu nedenle meme kanseri hücrelerinin tamoksifen duyarlılığını arttırmak üzerine çok sayıda çalışma sürdürülmektedir. Son çalışmalar, endoplazmik retikulum (ER) stresine ilişkin mekanizmaların meme kanserinin ilerlemesinde ve kazanılmış ilaç direncinde önemli anahtar düzenleyiciler olduğuna işaret etmiştir. Bu nedenle ER stresini modüle eden ajanlar meme kanserine yönelik geliştirilecek yeni tedavi yaklaşımları için yoğun olarak araştırılmaktadır. Çalışmalarımızda D/L-homosistein’in tamoksifen ile kombine uygulamasının in vitro da tamoksifene direnç gelişimini iyi mimik eden MCF-7/TAMR-1 hücrelerinde ER stresi modülasyonu yolu ile tamoksifen duyarlılığını geliştirdiği belirlenmiştir. Çalışmamızdan elde edilen bulgular meme kanserinde ER stresi ile ilişkili süreçlere etki edebilecek yeni moleküllerin tamoksifen ile kombine edilerek tamoksifen direncine karşı uygulanacak alternatif yaklaşımlar açısından umut vaat ettiğini önermektedir.

Keywords

• ER stresi
• MCF-7/TAMR-1
• Meme Kanseri
• Tamoksifen

References

1. [1] Rivenbark, A. G., O'Connor, S. M., Coleman, W. B. 2013. Molecular and cellular heterogeneity in breast cancer: challenges for personalized medicine. The American journal of pathology, 183(4), 1113–1124.
2. [2] Hong, R., Ma, F., Xu, B., Li, Q., Zhang, P., Yuan, P., Wang, J., Fan, Y., Cai, R. 2014. Efficacy of platinum-based chemotherapy in triple-negative breast cancer patients with metastases confined to the lungs: a single-institute experience. Anti-Cancer Drugs, 25(9),1089-1094.
3. [3] Viedma-Rodríguez, R., Baiza-Gutman, L., Salamanca-Gómez, F., Diaz-Zaragoza, M., Martínez-Hernández, G., Ruiz Esparza-Garrido, R., Velázquez-Flores, M. A., Arenas-Aranda, D. 2014. Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (review). Oncology reports, 32(1), 3–15.
4. [4] Chang, M. 2012. Tamoxifen resistance in breast cancer. Biomolecules & therapeutics, 20(3), 256–267.
5. [5] Dorssers, L. C., Van der Flier, S., Brinkman, A., van Agthoven, T., Veldscholte, J., Berns, E. M., Klijn, J. G., Beex, L. V., Foekens, J. A. 2001. Tamoxifen resistance in breast cancer: elucidating mechanisms. Drugs, 61(12), 1721–1733.
6. [6] Parkin, D. M., Bray, F., Ferlay, J., Pisani, P. 2005. Global cancer statistics, 2002. CA: a cancer journal for clinicians, 55(2), 74–108.
7. [7] Welch, G. N., Loscalzo, J. 1998. Homocysteine and atherothrombosis. The New England journal of medicine, 338(15), 1042–1050.
8. [8] Thambyrajah, J., Townend, J. N. 2000. Homocysteine and atherothrombosis-mechanisms for injury. European heart journal, 21(12), 967–974.

9. [9] Zou, C. G., Banerjee, R. 2005. Homocysteine and redox signaling. Antioxidants & redox signaling, 7(5-6), 547–559.
10. [10] Outinen, P. A., Sood, S. K., Pfeifer, S. I., Pamidi, S., Podor, T. J., Li, J., Weitz, J. I., Austin, R. C. 1999. Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood, 94(3), 959–967.
11. [11] Xu, D., Neville, R., Finkel, T. 2000. Homocysteine accelerates endothelial cell senescence. FEBS letters, 470(1), 20–24.
12. [12] Zhang, C., Cai, Y., Adachi, M. T., Oshiro, S., Aso, T., Kaufman, R. J., Kitajima, S. 2001. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. The Journal of biological chemistry, 276(38), 35867–35874.
13. [13] Kruman, I. I., Culmsee, C., Chan, S. L., Kruman, Y., Guo, Z., Penix, L., Mattson, M. P. 2000. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. The Journal of neuroscience, 20(18), 6920–6926.
14. [14] Adams, C. J., Kopp, M. C., Larburu, N., Nowak, P. R., Ali, M. 2019. Structure and molecular mechanism of ER stress signaling by the unfolded protein response signal activator IRE1. Frontiers in molecular biosciences, 6, 11.
15. [15] Hetz C. 2012. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nature reviews. Molecular cell biology, 13(2), 89–102.
16. [16] Zinszner, H., Kuroda, M., Wang, X., Batchvarova, N., Lightfoot, R. T., Remotti, H., Stevens, J. L., Ron, D. 1998. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes & development, 12(7), 982–995.
17. [17] McCullough, K. D., Martindale, J. L., Klotz, L. O., Aw, T. Y., Holbrook, N. J. 2001. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Molecular and cellular biology, 21(4), 1249–1259.
18. [18] Madden, E., Logue, S. E., Healy, S. J., Manie, S., Samali, A. 2019. The role of the unfolded protein response in cancer progression: From oncogenesis to chemoresistance. Biology of the cell, 111(1), 1–17.
19. [19] Robinson, C. M., Talty, A., Logue, S. E., Mnich, K., Gorman, A. M., Samali, A. 2021. An emerging role for the unfolded protein response in pancreatic cancer. Cancers, 13(2), 261.
20. [20] Romero-Ramirez, L., Cao, H., Regalado, M. P., Kambham, N., Siemann, D., Kim, J. J., Le, Q. T., Koong, A. C. 2009. X box-binding protein 1 regulates angiogenesis in human pancreatic adenocarcinomas. Translational oncology, 2(1), 31–38.
21. [21] Bahar, E., Kim, J. Y., Yoon, H. 2019. Chemotherapy resistance explained through endoplasmic reticulum stress-dependent signaling. Cancers, 11(3), 338.
22. [22] King, A. P., Wilson, J. J. 2020. Endoplasmic reticulum stress: an arising target for metal-based anticancer agents. Chemical Society reviews, 49(22), 8113–8136.
23. [23] Erzurumlu, Y., Ballar, P. 2017. Androgen mediated regulation of endoplasmic reticulum-associated degradation and its effects on prostate cancer. Scientific reports, 7, 40719.
24. [24] Werstuck, G. H., Lentz, S. R., Dayal, S., Hossain, G. S., Sood, S. K., Shi, Y. Y., Zhou, J., Maeda, N., Krisans, S. K., Malinow, M. R., Austin, R. C. 2001. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. The Journal of clinical investigation, 107(10), 1263.
25. [25] Yu, X., Lv, J., Zhu, Y., Duan, L., Ma, L. 2013. Homocysteine inhibits hepatocyte proliferation via endoplasmic reticulum stress. PLoS One, 8(1), e54265.
26. [26] Gartel A. L. 2006. Is p21 an oncogene?. Molecular cancer therapeutics, 5(6), 1385–1386.
27. [27] Bertoli, C., Skotheim, J. M., de Bruin, R. A. 2013. Control of cell cycle transcription during G1 and S phases. Nature reviews. Molecular cell biology, 14(8), 518–528.
28. [28] Lloyd, R. V., Erickson, L. A., Jin, L., Kulig, E., Qian, X., Cheville, J. C., Scheithauer, B. W. 1999. p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. The American journal of pathology, 154(2), 313–323.
29. [29] Vlach, J., Hennecke, S., Amati, B. 1997. Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. The EMBO journal, 16(17), 5334–5344.
30. [30] Jordan, V. C. 1992. The role of tamoxifen in the treatment and prevention of breast cancer. Current problems in cancer, 16(3), 129–176.
31. [31] Manna, S., Holz, M. K. 2016. Tamoxifen action in ER-negative breast cancer. Signal transduction insights, 5, 1–7.
32. [32] Vasan, N., Baselga, J., Hyman, D. M. 2019. A view on drug resistance in cancer. Nature, 575(7782), 299–309. [33] Strakova, J., Williams, K. T., Gupta, S., Schalinske, K. L., Kruger, W. D., Rozen, R., Jiracek, J., Li, L., Garrow, T. A. 2010. Dietary intake of S-(alpha-carboxybutyl)-DL-homocysteine induces hyperhomocysteinemia in rats. Nutrition research, 30(7), 492-500.
33. [34] Ming, J., Ruan, S., Wang, M., Ye, D., Fan, N., Meng, Q., Tian, B., Huang, T. 2015. A novel chemical, STF-083010, reverses tamoxifen-related drug resistance in breast cancer by inhibiting IRE1/XBP1. Oncotarget, 6(38), 40692–40703.
34. [35] Oyadomari, S., Mori, M. 2004. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell death and differentiation, 11(4), 381–389.