Green tea compounds in breast cancer prevention and treatment

Table 1 Studies of green tea catechins on mammary tumorigenesis in animal models or clinical trials

Ref.	Model	Intervention	Main results
Kavanagh et al[30], 2001	4-wk-old female Sprague-Dawley rats	Treated with green tea catechins after exposure to DMBA	Green tea extract given after initiation significantly increases mammary tumor latency and decreases tumor weight and metastases in DMBA-treated rats
Hirose et al[34], 2002	6-wk-old female F344 rats	PhIP alone or PhIP plus 1% green tea catechins for 52 wk	1% green tea catechins were associated only with reduced mean size of mammary tumors without affecting the total number of mammary tumors
Whitsett et al[35] ,2006	Female Sprague–Dawley CD rats	Treated with DMBA to induce breast cancer after previous exposure to green tea catechins or control diet throughout life	Animals exposed throughout life to EGCG in the drinking water showed a decrease in the latency to first tumor development, although there was no significant difference as compared with the control group with respect to second and third tumor latency. Furthermore, the number of tumors per rat in EGCG-exposed rats was not significantly different from the controls
Kaur et al[36], 2007	C3(1)SV40T, t antigen transgenic multiple mammary adenocarcinoma mice	Mice received green tea catechins in drinking water at 0.01% (w/v) for 25 wk, with water as control	Green tea catechins delayed carcinogenesis as evidenced by a significant decrease in the volume and size of tumors in the mice exposed to green tea extract
Lubet et al[37], 2007	50-d-old female Sprague-Dawley rats	Intravenous injection of methyl-nitrosourea (75 mg/kg bw) via the jugular vein. 5 d after treatment with the carcinogen, Poly E was given by gavage at 1000 and 333 mg/kg bw/d.	There was no effect of Poly E on the latency period of the mammary tumors. The high and low doses of Poly E decreased the number of mammary tumors by 14% and reduced the weight of the tumors by 30% and 21%, respectively
Sakata et al[31], 2011	C3H/OuJ mice carrying preneoplastic lesions	Treated with EGCG and tamoxifen alone or in combination	The tumor incidences were decreased in the green tea extract, tamoxifen, and green tea extract and tamoxifen groups. Importantly, in the group treated with green tea extract and tamoxifen, no tumors developed
Crew et al[32],2012	Women with a history of histologically confirmed resected stage I-III, estrogen and progesterone receptor negative breast carcinoma.	Participants received either Poly E delivering 400, 600, or 800 mg of EGCG (2-4 capsules) twice daily with food or matching placebo for 6 mo	(1) The MTD for Poly E should be 600 mg twice daily; (2) There was about a 70% reduction in serum estradiol levels (P = 0.05) and a significant decrease in SHBG (P = 0.03) at 6 mo compared with baseline in the Poly E group. However, these changes did not differ significantly compared with the placebo group due to smaller numbers; and (3) No changes in breast tissue proliferation were observed.

DMBA: Dimethyl-benzanthracene; EGCG: Epigallocatechin-3-gallate.

Table 2 Studies of green tea catechins on breast cancer treatment in animal models

Ref.	Model	Intervention	Effect on tumor size	Main mechanisms
Gu et al[39], 2013	8-wk-old female C57BL/6 mice were inoculated with 106 E0771 cells into the left fourth mammary gland fat pad	After cells were inoculated, mice received EGCG (around 50-100 mg/kg per day) in drinking water for 4 wk and 8 control mice received water only	(1) Tumor cross section area reduced 65% (P < 0.01); (2) tumour weight reduced 68% (P < 0.01); and (3) no difference in body weight, heart weight, kidney weight, or urinary protein	Inhibition of vascular endothelial growth factor (VEGF) expression and tumor angiogenesis via inhibiting hypoxia-inducible factor 1α and nuclear factor κB activation
Mineva et al[40], 2013	6-wk-old female nonobese diabetic/severe combined immunodeficiency mice were implanted with 5 × 103 SUM-149 cells in the fourth inguinal mammary fat pad	After 25 d, mice were intraperitoneally injected with 16.5 mg/kg EGCG or control PBS five times a week for the first five weeks and daily for the last week	(1) Tumor volume decreased 37.7% ± 4.4%; (2) tumor weight decreased 28.6% ± 6.5%; and (3) the lymphatic vessel density at the periphery of tumors decreased in EGCG-treated mice	EGCG decreased levels of VEGF-D RNA and VEGF-D protein
Jang et al[42], 2013	4T1 cells (105) were injected subcutaneously into either side of the posterior flank of BALB/c mice	On the 7th, 9th, 11th days after cell injection, mice were intraperitoneally injected with either EGCG (10 mg/kg) or PBS control	On day 30 after cell injection, a significant decrease of tumor volume and weight was observed in the EGCG-treated group vs the control group (P < 0.0005)	EGCG inhibited expression of CSF-1, CCL-2, IL-6 and transforming growth factor-β, and induced tumor necrosis factor-α expression
Thangapazham et al[43], 2007	5-wk-old female athymic nude mice (NCr-nu/nu) were implanted with 5 × 106 MDA-MB-231 cells in the mammary fat pad	After cell inoculation, one group of animals received 1% polyphenols from green tea (GTP) as a sole source of drinking water and the other group received a dose of 1 mg/animal of EGCG or water as control	At the end of 10 wk, the tumor volume was reduced by 45% and 61% in the EGCG and GTP treated groups, respectively (P < 0.05). All animals appeared healthy with no loss of body weight	EGCG and GTP fed animals showed increased apoptosis and decreased proliferation

DMBA: Dimethyl-benzanthracene; EGCG: Epigallocatechin-3-gallate; VEGF: Vascular endothelial growth factor.