Drug-resistant Stem Cell Models for the Hormone-responsive Luminal A Breast Cancer

Main Article Content

Nitin Telang


Background: Progression of early stage breast cancer to advanced stage metastatic disease represents a major cause of death in women. The Luminal A breast cancer subtype exhibits acceptable response to Chemo-endocrine and targeted therapy. However, these treatment options are associated with intrinsic/acquired therapy resistance and emergence chemo-resistant cancer initiating stem cell population, and resultant progression to advanced stage metastatic disease. These limitations emphasize an unmet need for the development of reliable models for cancer stem cells that facilitate identification of efficacious therapeutic alternatives. Documented human consumption, low systemic toxicity, preclinical cancer growth inhibitory efficacy and stem cell targeting efficacy of natural products, such as dietary phytochemicals and nutritional herbs, provide mechanistic leads for these agents as testable therapeutic alternatives. 

Objectives: The objectives of the present review are to i.) Provide a systematic discussion of published evidence relevant conceptual background of conventional/targeted therapy and nutritional herbs as testable alternatives, ii.) Growth inhibitory efficacy of nutritional herbs in a cellular model for the Luminal A breast cancer, iii.) Breast cancer stem cell biology and stem cell models for therapy-resistant breast cancer, and iv.) Future research directions.

Conclusions: Collectively, all the elements discussed in the present review validate mechanism-based experimental approaches to identify and prioritize potential therapeutic alternatives.

Future Research: This review provides a rationale for investigations on patient-derived tumor samples that may minimize extrapolation of the preclinical data for their clinical relevance and translatability.

Keywords: Cancer, Breast Cancer, Luminal A Breast Cancer, Hormone-responsive Luminal A Breast Cancer, Drug-resistant Stem Cell Models, Cell Models, Stem Cell Models, Drug-resistant

Article Details

How to Cite
TELANG, Nitin. Drug-resistant Stem Cell Models for the Hormone-responsive Luminal A Breast Cancer. Medical Research Archives, [S.l.], v. 11, n. 2, feb. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3556>. Date accessed: 16 apr. 2024. doi: https://doi.org/10.18103/mra.v11i2.3556.
Review Articles


1. American Cancer Society Facts and Figures-2022. American Cancer Society, Inc. Atlanta, GA, 2022.
2. Sorlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinoma distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. 2001, 98 (19): 10869-10874. DOI: 10.1073/pnas.191367098.
3. National Comprehensive Cancer Network 2022. http://www.nccn.org.
4. Mukherjee B, Telang N, Wong GYC: Growth inhibition of estrogen receptor positive human breast cancer cells by Taheebo from the inner bark of Tabebuia avellanedae tree. Int. J. Mol. Med. 2009, 24 (2): 253-260. DOI: 10.3892/ijmm_00000228.
5. Telang NT, Li G, Sepkovic DW, et al: Anti-proliferative effects of Chinese herb Cornus officinalis in a cell culture model for estrogen receptor positive clinical breast cancer. Mol. Med. Rep. 2012, 5 (1): 22-28. DOI: 10.3892/mmr.2011.617.
6. Telang NT, Li G, Sepkovic D, et al: Comparative efficacy of extracts from Lycium barbarum bark and fruit on estrogen receptor positive human mammary carcinoma MCF-7 cells. Nutr. Cancer 2014, 66 (2): 278-284. DOI: 10.1080/01635581.2014.864776.
7. Telang N, Li G, Katdare M, et al: Inhibitory effects of Chinese nutritional herbs in isogenic breast carcinoma cells with modulated estrogen receptor function. Oncol. Lett. 2016, 12 (5): 3949-3957. DOI: 10.3892/0l.2016.5197.
8. Telang NT, Li G, Katdare M, et al: The nutritional herb Epimedium grandiflorum inhibits the growth in a model for Luminal A molecular subtype of breast cancer. Oncol. Lett. 2017, 13 (4): 2477-2482. DOI: 10.3892/ol.2017.5720.
9. Telang N, Nair HB, Wong GYC: Growth inhibitory efficacy and anti-aromatase activity of Tabebuia avellanedae in a model for post-menopausal breast cancer. Biomed. Rep. 2019, 11 (5): 222-229. DOI: 10.3892/br.2019.1244.
10. Naujokat C, Mc Kee DI: The ‘Big Five’ phytochemicals targeting cancer stem cells: Curcumin, EGCG, sulforaphane, reserveratrol and genistein. Cur. Med. Chem. 2012, 28 (22): 4321-4342. DOI: 10.2174/0929867327666200228110738.
11. Hong M, Tan HY, Li S, et al: Cancer stem cells: Potential targets of Chinese medicines Chinese medicines and their active components. Int. J. Mol. Sci. 2016, 17: 893.
12. Manogaran P, Umapathy D, Karthikeyan M, et al: Dietary phytochemicals as a potential source of targeting cancer stem cells. Cancer Invest. 2021, 39 (4): 349-368. DOI: 10.1080/07357907.2021.1894569.
13. Meerson A, Khatib S, Mahjna J: Natural products targeting cancer stem cells for augmenting cancer therapeutics. Int. J. Mol. Sci. 2021, 22: 13044.
14. Telang N: Stem cell models for cancer therapy. Int. J. Mol. Sci. 2022, 23: 7055. DOI: 10.3390/ijms23137055.
15. Ye L, Jia Y, Ji KE, et al: Traditional Chinese medicines in prevention and treatment of breast cancer and metastasis. Oncol. Lett. 2015, 10 (3): 1240-1250. DOI: 10.3892/ol.2015.3459.
16. Yang Z, Zhang Q, Yu L, et al: The signaling pathways and targets of traditional Chinese medicine and natural medicine in triple-negative breast cancer. J. Ethno-pharmacology 2021, 264: 113249. DOI: 10.1016/jep.2020.113249.
17. Moy B, Goss PE: Estrogen receptor pathway: Resistance to endocrine therapy and new therapeutic approaches. Clin. Cancer Res. 2006, 12 (16): 4790-4793. DOI: 10.1158/1078-0432.CCR-06-1535.
18. O’Hara J, Vareslija D, Mc Brian J, et al: A1B1: ER-α transcriptional activity is selectively enhanced in aromatase inhibitor-resistant breast cancer cells. Clin Cancer Res. 2012, 18 (12): 3305-3315. DOI: 10.1158/1078-0423.CCR-11-3300.
19. Gupta M, McDugal A, Safe S: Estrogenic and anti-estrogenic activities of 16α- and 2-hydroxy metabolites of 17β-estradiol in MCF-7 and T47D human breast cancer cells. J. Steroid Biochem. Mol. Biol. 1998, 67 (5-6): 413-419. DOI: 10.1016/s0960-0760(98)00135-6.
20. Santen RJ, Yue W, Wang J-P: Estrogen metabolites and breast cancer. Steroids 2015, 99 (Pt A): 61-66. DOI: 10.1016/j.steroids.2014.08.003.
21. Suto A, Telang NT, Tanino H, et al: In vitro and in vivo modulation of growth regulation in the human breast cancer cell line MCF-7 by estradiol metabolites. Breast Cancer 1999, 6 (2): 87-92. DOI: 10.1007/BFO2966913.
22. Telang NT: The divergent effects of ovarian steroid hormones in the MCF-7 model for Luminal A breast cancer: Mechanistic leads for therapy. Int. J. Mol. Sci. 2022, 23: 4800. DOI: 10.3390/ijms23094800.
23. Barker N: Adult intestinal stem cells: Critical drivers of epithelial homeostasis and regeneration. Nat. Rev. Mol. Cell. Biol. 2014, 15 (1): 19-33. DOI: 10.1038/nrm3721.
24. Soteriou D, Fuchs Y: A matter of life and death: Stem cell survival in tissue regeneration and tumor formation. Nat. Rev. Cancer 2018, 18 (3): 187-201. DOI: 10.1038/nrc.2017.122.
25. Lytle NK, Barber AG, Reya T: Stem cell fate in cancer growth, progression and therapy resistance. Nat. Rev. Cancer 2018, 18 (11): 669-680. DOI: 10.1038/s41568-018-0056-x.
26. Yaeger R, Solit DB: Overcoming adaptive resistance to KRAS inhibitors through vertical pathway targeting. Clin. Cancer Res. 2020, 26 (7): 1538-1540, 2020. DOI: 10.1158/1078-0432.CCR-19-4060.
27. Shibue T, Weinberg RA: EMT, CSC and drug resistance. Nat. Rev. Clin. Oncol. 2017, 14 (10): 611-629. DOI: 10.1038/nrclinonc.2017.44.
28. Nunes T, Hamdan D, Leboeuf C, et al: Targeting cancer stem cells to overcome chemo-resistance. Int. J. Mol. Sci. 2018, 19: 4036.
29. Wook J: Role of JAK/STAT-3 signaling in in the regulation of metastasis, the transition of cancer stem cells, and chemo-resistance of cancer by epithelial-mesenchymal transition. Cells 2020, 9: 217. DOI: 10.3390/cells9010217.
30. Gooding AJ, Scheimann WP: Epithelial-mesenchymal transition programs and cancer stem cell phenotypes: mediators of breast cancer therapy resistance. Mol. Cancer Res. 2020, 18 (9): 1257-1270. DOI: 10.1158/1541-7786.MCR-20-0067.
31. Kanzaki H, Chatterjee A, Hosein H, et al: Disabling the nuclear trans-localization of RelA/NFkB by a small molecule inhibits triple-negative breast cancer growth. Breast Cancer (Dove Med. Press) 2021, 13: 419-430. DOI: 10.2147/BCTT.S310231.
32. Park IH, Zhou R, West JA, et al: Reprograming of human somatic cells to pluripotency with defined factors. Nature 2008, 451 (7175): 141-146. DOI: 10.1038/nature06534.
33. Yu J, Hu K, Smuga-Otto K, et al: Human induced pluripotent cells free of vector and transgene sequences. Science 2009, 324 (5928): 797-801. DOI: 10.1126/science.1172482.
34. Sabnis G, Brodie A: Understanding resistance to endocrine agents: Molecular mechanisms and potential for intervention. Clin. Breast Cancer 2010, 10 (1): E6-E15. DOI: 10.3816/CBC.2010.n.014.
35. Hole S, Pedersen AM, Hansen SK, et al: New cell culture model for aromatase inhibitor-resistant breast cancer shows sensitivity to fulvestrant treatment and cross-resistance between letrozole and exemestane. Int. J. Oncol.2015, 46 (4): 1481-1490. DOI: 10.3892/ijo.2015.2850.
36. Fragiadaki P, Ranieri E, Kalliantasi K, et al: Telomerase inhibition and activation: A systematic review. Mol. Med. Rep. 2022, 25 (5): 158. DOI: 10.3892/mmr.2022.12674.
37. Kumar VE, Nambiar R, De Souza C, et al: Targeting epigenetic modifiers of tumor plasticity and stem cell behavior. Cells 2020, 11: 1403. DOI: 10.3390/cells11091403.
38. Bruna A, Rueda OM, Greenwood W, et al: A biobank of breast cancer explants with preserved intra-tumor heterogeneity to screen anti-cancer compounds. Cell 2016, 167 (1): 260-274. DOI: 10.1016/j.cell.2016.08.041.
39. Drost J, Clevers H: Organoids in cancer research. Nat. Rev. Cancer 2018, 18 (7): 407-418. DOI: 10.1038/s41568-018-0007-6.