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Licorice Root Components and Breast Cancer Metastasis

Michelle

1
Wang ,

Yunxian Liu , Xujuan

1
Yang ,

James A.

1
Hartman ,

Rita

1
Strakovsky ,

Daniel R.

2
Doerge

and William G.

1
Helferich

1Department

of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign


2Division of Biochemical Toxicology, National Center for Toxicological Research, US FDA

ABSTRACT
Breast cancer is the most common cancer affecting women in the United States, and
the development of metastasis in these patients leads to poor prognosis and survival.
Licorice root and licorice root components have been shown to have the potential for
reducing cancer growth in certain breast cancer animal models. However, standard
rodent diet is not representative of the percentage of fat consumed in an average diet,
and therefore studies using high-fat diets are warranted. Here, we investigate the
progression of breast cancer metastasis in a mouse model using a spontaneous
syngeneic mouse line, 4T1, when supplemented with licorice root components and a
high fat-diet. In animals fed a low-fat diet, licorice root powder and isoliquiritigenin,
but not licorice root extract, reduced the incidence of lung tumor nodules in mice. In
animals fed a high-fat diet, licorice root powder, licorice root extract and
isoliquiritigenin had no significant effect on the number of lung tumor nodules in mice.

5) In a low fat diet, liver weight


was significantly increased with
supplementation of licorice root
powder.
Licorice Root Powder
(LRP)

Licorice Root Extract (LRE) Isoliquiritigenin (ILQ)

a
b
c

1) BLI monitoring of metastasis progression: 4T1 cells formed primary tumors in


the tibial bone first, and then metastasized to the lungs.

7) Licorice root powder increased liver weights in animals independent


of low or high fat diet. (*** p<0.005)

OBJECTIVE
Our aim is to study the possible interaction effect between a high fat diet and
supplementation of licorice root botanicals in a metastatic breast cancer model.

a
b

RESULTS

6) In a high fat diet, liver weight


was significantly increased with
supplementation of licorice root
powder.

A single mouse was imaged by BLI on day 6, 8, 12, 16 and 20 after cell injection. D6: signals from
bone primary tumors became detectable; D8: signals from metastasized lung tumors became
detectable; D12 to D20: signals from primary and metastasized tumors increased to saturation.

***

***

***

INTRODUCTION
Licorice root has been used in Eastern and Western cultures for centuries as a remedy
for a variety of ailments such as stomach ulcer, bronchitis, asthma and sore throat.1
More recently, licorice root and its constituents have been demonstrated to reduce cell
proliferation in vitro2 and the extent and frequency of metastasis in vivo.3 Conversely,
high fat diets have been implicated in increasing tumor growth and metastasis.4 A
standard AIN-93G rodent diet provides 16% kcal from fat and is not representative of
the average American population, who consume approximately 33.5% kcal from fat.5
So far, the consequences of consuming a high fat diet in conjunction with licorice root
compounds on the progression of breast cancer metastasis are unknown.

MATERIALS & METHODS


In this model, we mimicked late stage metastatic progression of breast cancer using
the spontaneous syngeneic 4T1 cell line (1,000 cells per mouse) suspended in 2.5 L
matrigel and injected into the tibia of ovariectomized Balb/C mice. Animals were
prefed AIN93G (16% fat) or modified AIN93G( 45% fat) diets for 2 weeks before
beginning diets supplemented with licorice root powder (LRP), licorice root extract
(LRE), isoliquiritigenin (ILQ) or no compound, which were supplied ad libitum to
animals after cell injection until sacrifice. Body weights and food intake were
monitored weekly throughout the study, as well as metastastic progression bi-weekly
using Bioluminescent Imaging (BLI). At necropsy, blood was drawn for serum analysis.
Liver, uterus, and gonadal tissue were collected for weight and flash-frozen. Lungs
were fixed and tumor nodules on the lung surface were counted. Lungs were then
embedded in paraffin for H&E staining.

2) Number of lung tumor nodules


were reduced in animals fed low fat
diets supplemented with powder and
ILQ, but no difference with extract.

3) No significant difference found in


number of lung tumor nodules in
animals fed high fat diets supplemented
with powder, extract or ILQ.

CONCLUSION
a
ab

c
bc

4) Tumor lung count was significantly increased in high fat diet


supplemented with powder and ILQ compared with a low fat diet.
P=0.16

P=0.002**

P=0.003**

Most American diets will contain about 30-40% kcal from fat. We looked at the
effects of licorice root and licorice root components on the progression of
metastatic breast cancer in a low and high fat diet. Licorice root and licorice
root compounds decreased the incidence of breast tumor nodules in the lung
when supplemented in a low fat diet but had no effect in a high fat diet. Twoway ANOVA showed significant interaction effects between low and high fat
diets and licorice root components (p=0.025). Licorice root powder but not
licorice root extract or isoliquiritigenin increased liver weights in both low and
high fat diets. More research is needed to determine possible mechanisms.
References
1National Center for Complementary and Alternative Medicine. Licorice Root. National Center for Complementary and Alternative Medicine
Web site. Accessed at http://nccam.nih.gov/health/licoriceroot on Oct 15, 2013.
2Wang Zhiyu, Wang Neng, Han Shouwei, Wang Dongmei, Mo Suilin, Yu Linzhong, Huang Hui, Tsui Kamchuen, Shen Jiangan, and Chen Jianping.
Dietary Compound Isoliquiritigenin Inhibits Breast Cancer Neoangiogenisis via VEGF/VEGFR-2 Signaling Pathway. PlosOne. 2013;8(7).
3Lee Sun Kyoung, Park Kwang-Kyun, Park Jung Han Yoon, Lim Soon Sung and Chung Won-Yoon. The Inhibitory Effect of Roasted Licorice Extract
on Human Metastatic Breast Cancer Cell-Induced Bone Destruction. Phytotherapy Research. 2013.
4Kim Eun Ji, Choi Mi-Ran, Park Heesook, Kim Minhee, Hong Ji Eun, Lee Jae-Yong, Chun Hyang Sook, Lee Ki Won, Park Jung Han Yoon. Dietary
fat increases solid tumor growth and metastasis of 4T1 murine mammary carcinoma cells and mortality in obesity resistant BALB/c mice.
Breast Cancer Research. 2011; 13:R78.
5Wright JD, Wang C-Y. Trends in intake of energy and macronutrients in adults from 1999-2000 through 2007-2008. NCHS data brief, no 49.
Hyattsville, MD: National Center for Health Statistics. 2010

ACKNOWLEDGEMENTS
This project was made possible by Grant Number P50AT006268 from the National Center for Complementary and
Alternative Medicines (NCCAM), the Office of Dietary Supplements (ODS) and the National Cancer Institute (NCI). Its
contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM,
ODS, NCI, or the National Institutes of Health.

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