Baicalein, unlike 4-hydroxytamoxifen but similar to G15, suppresses 17β-estradiol-induced cell invasion, and matrix metalloproteinase-9 expression and activation in MCF-7 human breast cancer cells

Chen,Yan; Hong,Duan‑Yang; Wang,Jing; Ling‑Hu,Jun; Zhang,Yan‑Yan; Pan,Di; Xu,Yi‑Ni; Tao,Ling; Luo,Hong; Shen,Xiang‑Chun

doi:10.3892/ol.2017.6298

Baicalein, unlike 4-hydroxytamoxifen but similar to G15, suppresses 17β-estradiol-induced cell invasion, and matrix metalloproteinase-9 expression and activation in MCF-7 human breast cancer cells

Authors:
- Yan Chen
- Duan‑Yang Hong
- Jing Wang
- Jun Ling‑Hu
- Yan‑Yan Zhang
- Di Pan
- Yi‑Ni Xu
- Ling Tao
- Hong Luo
- Xiang‑Chun Shen
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Affiliations: Key Laboratory of Optimal Utilization of Natural Medicine Resources, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China, Department of Pharmacology of Chinese Materia Medica, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
Published online on: June 2, 2017 https://doi.org/10.3892/ol.2017.6298
Pages: 1823-1830

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Abstract

Estrogen performs an important role in the growth and development of breast cancer. There are at least three major receptors, including estrogen receptor (ER)α and β, and G protein‑coupled receptor 30 (GPR30), which mediate the actions of estrogen through using transcriptional and rapid non‑genomic signaling pathways. Flavonoids have been considered candidates for chemopreventive agents in breast cancer. Baicalein, the primary flavonoid derived from the root of Scutellaria baicalensis Georgi, has been reported to exert an anti‑estrogenic effect. In the present study, the effects of baicalein on 17β‑estradiol (E2)‑induced cell invasion, and matrix metalloproteinase‑9 (MMP‑9) expression and activation were investigated. Furthermore, its effects were compared with that of the active form of the ER modulator tamoxifen 4‑hydroxytamoxifen (OHT) and the GPR30 antagonist G15 in ERα‑ and GPR30‑positive MCF‑7 breast cancer cells. The results demonstrated that OHT failed to prevent E2‑induced cell invasion, upregulation and proteolytic activity of MMP‑9. However, baicalein was able to significantly suppress these E2‑induced effects. Furthermore, E2‑stimulated invasion, and MMP‑9 expression and activation were significantly attenuated following G15 treatment. In addition, baicalein significantly inhibited G‑1, a specific GPR30 agonist, induced invasion, and reduced G‑1 promoted expression and activity of MMP‑9, consistent with effects of G15. The results of the present study suggest that baicalein is a therapeutic candidate for GPR30‑positive breast cancer treatment, and besides ERα targeting the GPR30 receptor it may achieve additional therapeutic benefits in breast cancer.

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1	Cordera F and Jordan VC: Steroid receptors and their role in the biology and control of breast cancer growth. Semin Oncol. 33:631–641. 2006. View Article : Google Scholar : PubMed/NCBI
2	Huang B, Warner M and Gustafsson JÅ: Estrogen receptors in breast carcinogenesis and endocrine therapy. Mol Cell Endocrinol. 418:240–244. 2015. View Article : Google Scholar : PubMed/NCBI
3	Johnston SR: New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res. 16:1979–1987. 2010. View Article : Google Scholar : PubMed/NCBI
4	Jager NG, Linn SC, Schellens JH and Beijnen JH: Tailored tamoxifen treatment for breast cancer patients: A perspective. Clin Breast Cancer. 15:241–244. 2015. View Article : Google Scholar : PubMed/NCBI
5	Prossnitz ER and Arterburn JB: International union of basic and clinical pharmacology. XCVII. G protein-coupled estrogen receptor and its pharmacologic modulators. Pharmacol Rev. 67:505–540. 2015. View Article : Google Scholar : PubMed/NCBI
6	Filardo EJ, Graeber CT, Quinn JA, Resnick MB, Giri D, DeLellis RA, Steinhoff MM and Sabo E: Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin Cancer Res. 12:6359–6366. 2006. View Article : Google Scholar : PubMed/NCBI
7	Liu Q, Li JG, Zheng XY, Jin F and Dong HT: Expression of CD133, PAX2, ESA, and GPR30 in invasive ductal breast carcinomas. Chin Med J (Engl). 122:2763–2769. 2009.PubMed/NCBI
8	Marjon NA, Hu C, Hathaway HJ and Prossnitz ER: G protein-coupled estrogen receptor regulates mammary tumorigenesis and metastasis. Mol Cancer Res. 12:1644–1654. 2014. View Article : Google Scholar : PubMed/NCBI
9	Revankar CM, Cimino DF, Sklar LA, Arterburn JB and Prossnitz ER: A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 307:1625–1630. 2005. View Article : Google Scholar : PubMed/NCBI
10	Yilmaz M, Christofori G and Lehembre F: Distinct mechanisms of tumor invasion and metastasis. Trends Mol Med. 13:535–541. 2007. View Article : Google Scholar : PubMed/NCBI
11	Kessenbrock K, Plaks V and Werb Z: Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell. 141:52–67. 2010. View Article : Google Scholar : PubMed/NCBI
12	Li HC, Cao DC, Liu Y, Hou YF, Wu J, Lu JS, Di GH, Liu G, Li FM, Ou ZL, et al: Prognostic value of matrix metalloproteinases (MMP-2 and MMP-9) in patients with lymph node-negative breast carcinoma. Breast Cancer Res Treat. 88:75–85. 2004. View Article : Google Scholar : PubMed/NCBI
13	Liu HD, Yan Y, Cao XF, Tan PZ, Wen HX, Lv CM, Li XM and Liu GY: The expression of a novel estrogen receptor, GPR30, in epithelial ovarian carcinoma and its correlation with MMP-9. Sheng Li Xue Bao. 62:524–528. 2010.(In Chinese). PubMed/NCBI
14	Long L, Cao Y and Tang LD: Transmembrane estrogen receptor GPR30 is more frequently expressed in malignant than benign ovarian endometriotic cysts and correlates with MMP-9 expression. Int J Gynecol Cancer. 22:539–545. 2012. View Article : Google Scholar : PubMed/NCBI
15	Yan Y, Liu H, Wen H, Jiang X, Cao X, Zhang G and Liu G: The novel estrogen receptor GPER regulates the migration and invasion of ovarian cancer cells. Mol Cell Biochem. 378:1–7. 2013. View Article : Google Scholar : PubMed/NCBI
16	Rossi RE, Pericleous M, Mandair D, Whyand T and Caplin ME: The role of dietary factors in prevention and progression of breast cancer. Anticancer Res. 34:6861–6875. 2014.PubMed/NCBI
17	Hui C, Qi X, Qianyong Z, Xiaoli P, Jundong Z and Mantian M: Flavonoids, flavonoid subclasses and breast cancer risk: A meta-analysis of epidemiologic studies. PLoS One. 8:e543182013. View Article : Google Scholar : PubMed/NCBI
18	Cho YA, Kim J, Park KS, Lim SY, Shin A, Sung MK and Ro J: Effect of dietary soy intake on breast cancer risk according to menopause and hormone receptor status. Eur J Clin Nutr. 64:924–932. 2010. View Article : Google Scholar : PubMed/NCBI
19	Takemura H, Sakakibara H, Yamazaki S and Shimoi K: Breast cancer and flavonoids - a role in prevention. Curr Pharm Des. 19:6125–6132. 2013. View Article : Google Scholar : PubMed/NCBI
20	Moon YJ, Wang X and Morris ME: Dietary flavonoids: Effects on xenobiotic and carcinogen metabolism. Toxicol In Vitro. 20:187–210. 2006. View Article : Google Scholar : PubMed/NCBI
21	Po LS, Chen ZY, Tsang DS and Leung LK: Baicalein and genistein display differential actions on estrogen receptor (ER) transactivation and apoptosis in MCF-7 cells. Cancer Lett. 187:33–40. 2002. View Article : Google Scholar : PubMed/NCBI
22	Chang HT, Chou CT, Kuo DH, Shieh P, Jan CR and Liang WZ: The mechanism of Ca(2+) movement in the involvement of baicalein-induced cytotoxicity in ZR-75-1 human breast cancer cells. J Nat Prod. 78:1624–1634. 2015. View Article : Google Scholar : PubMed/NCBI
23	Shang D, Li Z, Zhu Z, Chen H, Zhao L, Wang X and Chen Y: Baicalein suppresses 17-β-estradiol-induced migration, adhesion and invasion of breast cancer cells via the G protein-coupled receptor 30 signaling pathway. Oncol Rep. 33:2077–2085. 2015.PubMed/NCBI
24	Wang L, Ling Y, Chen Y, Li CL, Feng F, You QD, Lu N and Guo QL: Flavonoid baicalein suppresses adhesion, migration and invasion of MDA-MB-231 human breast cancer cells. Cancer Lett. 297:42–48. 2010. View Article : Google Scholar : PubMed/NCBI
25	Chen P, Lu N, Ling Y, Chen Y, Hui H, Lu Z, Song X, Li Z, You Q and Guo Q: Inhibitory effects of wogonin on the invasion of human breast carcinoma cells by downregulating the expression and activity of matrix metalloproteinase-9. Toxicology. 282:122–128. 2011. View Article : Google Scholar : PubMed/NCBI
26	Pello OM, De Pizzol M, Mirolo M, Soucek L, Zammataro L, Amabile A, Doni A, Nebuloni M, Swigart LB, Evan GI, et al: Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. Blood. 119:411–421. 2012. View Article : Google Scholar : PubMed/NCBI
27	Ferreira E and Cronjé MJ: Selection of suitable reference genes for quantitative real-time PCR in apoptosis-induced MCF-7 breast cancer cells. Mol Biotechnol. 50:121–128. 2012. View Article : Google Scholar : PubMed/NCBI
28	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
29	Gialeli C, Theocharis AD and Karamanos NK: Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 278:16–27. 2011. View Article : Google Scholar : PubMed/NCBI
30	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
31	Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, Buyse M, Baum M, Buzdar A, Colleoni M, et al: Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 28:509–518. 2010. View Article : Google Scholar : PubMed/NCBI
32	Maggiolini M and Picard D: The unfolding stories of GPR30, a new membrane-bound estrogen receptor. J Endocrinol. 204:105–114. 2010. View Article : Google Scholar : PubMed/NCBI
33	Wang D, Hu L, Zhang G, Zhang L and Chen C: G protein-coupled receptor 30 in tumor development. Endocrine. 38:29–37. 2010. View Article : Google Scholar : PubMed/NCBI
34	Catalano S, Giordano C, Panza S, Chemi F, Bonofiglio D, Lanzino M, Rizza P, Romeo F, Fuqua SA, Maggiolini M, et al: Tamoxifen through GPER upregulates aromatase expression: A novel mechanism sustaining tamoxifen-resistant breast cancer cell growth. Breast Cancer Res Treat. 146:273–285. 2014. View Article : Google Scholar : PubMed/NCBI
35	Ruan SQ, Wang ZH, Wang SW, Fu ZX, Xu KL, Li DB and Zhang SZ: Heregulin-β1-induced GPR30 upregulation promotes the migration and invasion potential of SkBr3 breast cancer cells via ErbB2/ErbB3-MAPK/ERK pathway. Biochem Biophys Res Commun. 420:385–390. 2012. View Article : Google Scholar : PubMed/NCBI
36	Du GQ, Zhou L, Chen XY, Wan XP and He YY: The G protein-coupled receptor GPR30 mediates the proliferative and invasive effects induced by hydroxytamoxifen in endometrial cancer cells. Biochem Biophys Res Commun. 420:343–349. 2012. View Article : Google Scholar : PubMed/NCBI
37	Thompson EW, Reich R, Shima TB, Albini A, Graf J, Martin GR, Dickson RB and Lippman ME: Differential regulation of growth and invasiveness of MCF-7 breast cancer cells by antiestrogens. Cancer Res. 48:6764–6768. 1988.PubMed/NCBI
38	Nilsson UW, Garvin S and Dabrosin C: MMP-2 and MMP-9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells. Breast Cancer Res Treat. 102:253–261. 2007. View Article : Google Scholar : PubMed/NCBI
39	Fedele P, Calvani N, Marino A, Orlando L, Schiavone P, Quaranta A and Cinieri S: Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: Where are we now and where are we going? Crit Rev Oncol Hematol. 84:243–251. 2012. View Article : Google Scholar : PubMed/NCBI
40	Ignatov A, Ignatov T, Weissenborn C, Eggemann H, Bischoff J, Semczuk A, Roessner A, Costa SD and Kalinski T: G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer. Breast Cancer Res Treat. 128:457–466. 2011. View Article : Google Scholar : PubMed/NCBI
41	Mo Z, Liu M, Yang F, Luo H, Li Z, Tu G and Yang G: GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer. Breast Cancer Res. 15:R1142013. View Article : Google Scholar : PubMed/NCBI
42	Lin CW, Yang LY, Shen SC and Chen YC: IGF-I plus E2 induces proliferation via activation of ROS-dependent ERKs and JNKs in human breast carcinoma cells. J Cell Physiol. 212:666–674. 2007. View Article : Google Scholar : PubMed/NCBI
43	Branham WS, Dial SL, Moland CL, Hass BS, Blair RM, Fang H, Shi L, Tong W, Perkins RG and Sheehan DM: Phytoestrogens and mycoestrogens bind to the rat uterine estrogen receptor. J Nutr. 132:658–664. 2002.PubMed/NCBI
44	Shenouda NS, Zhou C, Browning JD, Ansell PJ, Sakla MS, Lubahn DB and Macdonald RS: Phytoestrogens in common herbs regulate prostate cancer cell growth in vitro. Nutr Cancer. 49:200–208. 2004. View Article : Google Scholar : PubMed/NCBI