Tumor microenvironmental growth factors induce long-term estrogen deprivation resistance in breast cancer
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Hormonal therapy is an effective treatment for luminal-like breast cancer. Aromatase inhibitor (AI) is widely used for estrogen receptor-positive, postmenopausal breast cancers. However, resistance is occurred and becomes a serious clinical concern. In general, progression of cancer strongly depends on tumor microenvironment, which may, therefore, also contribute to the development of AI resistance.
We evaluated tumor microenvironment-derived factors with respect to AI resistance using typical estrogen receptor-positive breast cancer cell lines. We established tumor microenvironment-dependent AI-resistant models and elucidated the underlying mechanisms.
T-47D cells had a higher dependence on microenvironment-derived factors, such as estrogen or growth factors, for survival than MCF-7 cells. We, therefore, evaluated tumor microenvironment growth factors with respect to AI resistance using T-47D cells. We established three resistant cell lines (V1, V2, and V3) that survived estrogen deprivation and growth factor-supplemented conditions. These cell lines were deficient in estrogen receptor α expression and estrogen-dependent growth. Among six representative growth factors, epidermal growth factor was the most influential. In these models, HER2 protein was overexpressed without gene amplification and intracellular phosphorylation pathways were activated compared to parental cell lines. Molecular targeting inhibitors revealed that V1 and V2 primarily rely on the PI3 K pathway for survival, whereas V3 relies on the MAPK pathway.
This study demonstrates the importance of tumor microenvironment-derived factors for the development of AI resistance. These resistant models did not utilize the same resistance mechanism, suggesting that flexible strategies are essential in conquering resistance.
KeywordsBreast cancer Aromatase inhibitor Hormonal therapy resistance Tumor microenvironment
This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan, a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan, the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO), and a grant from the Smoking Research Foundation.
Compliance with ethical standards
Conflict of interest
Shin-ichi Hayashi received research grants from Novartis Pharma K.K, Astra Zeneca K.K, and Eisai K.K.
- 4.Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res. 1991;51(15):3867–73.Google Scholar
- 10.Shee K, Yang W, Hinds JW, Hampsch RA, Varn FS, Traphagen NA, Patel K, Cheng C, Jenkins NP, Kettenbach AN, Demidenko E, Owens P, Faber AC, Golub TR, Straussman R, Miller TW. Therapeutically targeting tumor microenvironment- mediated drug resistance in estrogen receptor-positive breast cancer. J Exp Med. 2018;215(3):1–16.Google Scholar
- 11.Grugan KD, Miller CG, Yao Y, Michaylira CZ, Ohashi S, Klein-Szanto AJ, Diehl JA, Herlyn M, Han M, Nakagawa H, Rustgi AK. Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion. Proc Natl Acad Sci. 2010;107(24):11026–31.PubMedPubMedCentralGoogle Scholar
- 12.Roswall P, Bocci M, Bartoschek M, Li H, Kristiansen G, Jansson S, Lehn S, Sjölund J, Reid S, Larsson C, Eriksson P, Anderberg C, Cortez E, Saal LH, Orsmark-Pietras C, Cordero E, Haller BK, Häkkinen J, Burvenich IJG, Lim E, Orimo A, Höglund M, Rydén L, Moch H, Scott AM, Eriksson U, Pietras K. Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling. Nat Med. 2018;24(4):463–73.PubMedPubMedCentralGoogle Scholar
- 19.Fujiki N, Konno H, Kaneko Y, Gohno T, Hanamura T, Imami K, Ishihama Y, Nakanishi K, Niwa T, Seino Y, Yamaguchi Y, Hayashi S. Estrogen response element-GFP (ERE-GFP) introduced MCF-7 cells demonstrated the coexistence of multiple estrogen-deprivation resistant mechanisms. J Steroid Biochem Mol Biol. 2014;139:61–72.PubMedPubMedCentralGoogle Scholar
- 20.Hanamura T, Niwa T, Nishikawa S, Konno H, Gohno T, Tazawa C, Kobayashi Y, Kurosumi M, Takei H, Yamaguchi Y, Ito K-I, Hayashi S-I. Androgen metabolite-dependent growth of hormone receptor-positive breast cancer as a possible aromatase inhibitor-resistance mechanism. Breast Cancer Res Treat. 2013;139(3):731–40.PubMedPubMedCentralGoogle Scholar
- 22.Fujii R, Hanamura T, Suzuki T, Gohno T, Shibahara Y, Niwa T, Yamaguchi Y, Ohnuki K, Kakugawa Y, Hirakawa H, Ishida T, Sasano H, Ohuchi N, Hayashi S. Increased androgen receptor activity and cell proliferation in aromatase inhibitor-resistant breast carcinoma. J Steroid Biochem Mol Biol. 2014;144(Pt B):513–22.PubMedPubMedCentralGoogle Scholar
- 23.Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe JP, Tong F, Speed T, Spellman PT, DeVries S, Lapuk A, Wang NJ, Kuo WL, Stilwell JL, Pinkel D, Albertson DG, Waldman FM, McCormick F, Dickson RB, Johnson MD, Lippman M, Ethier S, Gazdar A, Gray JW. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006;10(6):515–27.PubMedPubMedCentralGoogle Scholar
- 27.Shibata T, Watari K, Izumi H, Kawahara A, Hattori S, Fukumitsu C, Murakami Y, Takahashi R, Toh U, Ito K, Ohdo S, Tanaka M, Kage M, Kuwano M, Ono M. Breast cancer resistance to antiestrogens is enhanced by increased ER degradation and ERBB2 expression. Cancer Res. 2017;77(2):545–56.PubMedPubMedCentralGoogle Scholar
- 28.Miller TW, Hennessy BT, González-Angulo AM, Fox EM, Mills GB, Chen H, Higham C, García-Echeverría C, Shyr Y, Arteaga CL. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120(7):2406–13.PubMedPubMedCentralGoogle Scholar
- 29.Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM, Parker JS, Miller MA, Huntsman DG, Lin L, Snider J, Davies SR, Olson JA, Watson MA, Saporita A, Weber JD, Ellis MJ. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 2009;69(9):3955–62.PubMedPubMedCentralGoogle Scholar
- 30.Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer. N Engl J Med. 2012;366(6):520–9.PubMedPubMedCentralGoogle Scholar
- 31.Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, Noguchi S, Perez A, Rugo HS, Deleu I, Burris HA, Provencher L, Neven P, Gnant M, Shtivelband M, Wu C, Fan J, Feng W, Taran T, Baselga J. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol. 2014;25(12):2357–62.PubMedPubMedCentralGoogle Scholar
- 34.Frogne T, Benjaminsen RV, Sonne-Hansen K, Sorensen BS, Nexo E, Laenkholm A-V, Rasmussen LM, Riese DJ, de Cremoux P, Stenvang J, Lykkesfeldt AE. Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat. 2009;114(2):263–75.PubMedGoogle Scholar