Exercise is thought to have a significant effect on chemotherapy, and previous studies have reported that exercise can increase patient survival. Thus, in this review, we aimed to summarize various animal models to analyze the effects of exercise on breast cancer.
We summarized types of breast cancer animal models from various reports and analyzed the effects of exercise on anti-cancer factors in breast cancer animal models.
This review aimed to systematically investigate if exercise could aid in suppressing breast cancer. Our study includes (a) increase in survival rate through exercise; (b) the intensity of exercise should be consistent and increased; (c) a mechanism for inhibiting carcinogenesis through exercise; (d) effects of exercise on anti-cancer function.
This review suggested the necessity of a variety of animal models for preclinical studies prior to breast cancer clinical trials. It also provides evidence to support the view that exercise plays an important role in the prevention or treatment of breast cancer by influencing anticancer factors.
Non-communicable diseases, as chronic diseases, account for 70% of the mortality rates worldwide, while communicable diseases cause the remaining 30%. Among non-communicable diseases, those with high mortality rates include cancer, diabetes, cardiovascular disease, and lung disease. Cancer is classified as a fatal disease for patients because it is difficult to cure owing to its rapid growth, and is highly likely to spread throughout the body through blood or lymphatic fluid. In particular, reduction of female physical activity due to various social environments is a potential cause of increased breast cancer incidence. In addition, the most frequent characteristic of breast cancer among women is not only high incidence, but also high efficiency of cancer treatment. Although the effectiveness of anti-cancer drugs is very high for breast cancer patients, a lot of pain, caused by chemotherapy, accompanies it. Therefore, there is an urgent need to improve the survival rate of breast cancer patients, and improve the quality of life during chemotherapy treatment. Recently, various preclinical studies have suggested that exercise attenuates tumor growth and tumorigenesis (
Mouse |
Mouse | Induction | Exercise | Protocols | Test | Efficacy & Signal pathways | Ref |
---|---|---|---|---|---|---|---|
Xenograft | NMRI-Foxn1nu | MCF-7 cell |
Running | Voluntary wheel |
-Tumor growth |
- MCF-7 (–36%, P <0.05) and |
4 |
Orthotopic | FVB/NJ | p53/PTEN |
Stretching | Treated for 10 minutes |
Tumor growth | 52% reduced tumor size | 5 |
Xenograft | Female BALB/c | MC4-L2 cell |
Running | Using the treadmill; |
- Tumor volume |
- Decrease tumor volume and |
6 |
Orthotopic | Female |
E0771 cell |
Running | Voluntary wheel running | - Tumor growth & |
- Increasing log phase tumor |
7 |
Orthotopic | Female FVB/NJ |
C3(1)SV40Tag |
Running | Using the treadmill; |
-Tumor growth |
- 771 (0.5 folds), C3(1) |
8 |
Orthotopic | Female |
4T1 cell |
Running | Wheels (running group) |
-Tumor growth, perfusion, |
-Statistically significantly reduced |
9 |
Xenograft | Female |
4T1 cell | Running | Using the treadmill (18 |
-Tumor growth |
- Exercise regulates tumor |
10 |
Orthotopic | Female |
4T1 cell | Running | Low intensity exercise (6 |
- Tumor growth |
- HE inhibited tumor growth |
11 |
Orthotopic | Female |
4T1 cell | Running | voluntary exercise four |
-Tumor growth | - Beneficial effects of voluntary |
12 |
Orthotopic | BALB/cBy | 4T1 cell | Running | Using the wheel running: |
-Tumor growth | -Running longer distances is |
13 |
Xenograft | Female |
MCF-7 cell |
Running | Using the wheel |
-Gene expression | -Exercise decrease the IL- |
14 |
Transgenic |
FVB/NJ |
Genetically predisposed |
Running | Voluntary wheel running |
-Voluntary physical |
-C2(1)/SV40Tag mice < FVB/ |
15 |
Transgenic |
p53-deficient |
Genetically predisposed |
Running | 1) voluntary wheel running |
-p53 expression |
-Con = TREX1 =TREX2 / Con |
16 |
Orthotopic | Athymic | MDA-MB-231 cell | Running | Voluntary wheel running |
- Survival |
- Con = Exercise |
17 |
Transgenic |
MMTV-PyMT |
Genetically predisposed |
Running | Voluntary wheel running | -Tumor growth |
-Con > Exercise |
18 |
Orthotopic | Female |
4T1 cell | Running | Treadmill running |
-Carbohydrate oxidation |
-Decrease the carbohydrate |
19 |
Xenograft | Female |
MC4-L2 cell |
Running | 6-18 m/min for 20-30 |
-Gene expression | The lowest level of IL-6, |
20 |
Xenograft | Female |
4T1 cell | Running | Endurance-trained for |
-Tumor growth |
-Exercise has -17% growth |
21 |
Xenograft | Female |
4T1 cell | Running | Using the treadmill; |
-Gene expression | -Anti-inflammation : IL-10/ |
22 |
Xenograft | Female |
4T1 cell | Swimming | Swim training 5 days/ |
-Gene expression | -Th1 systemic response ; |
23 |
Xenograft | Female |
4T1 cell | Running | 4 weeks of high-intensity |
-Tumor growth |
HIIT is associated with a |
24 |
Xenograft | Female |
MC4-L2 cell | Running | Treadmill |
-Gene expression | -miR-21 pathways; reduced |
25 |
Xenograft | Female |
EO771 breast |
Running | Reached maximum |
-Tumor hyposia, |
unknown | 26 |
Xenograft | Athymic | MDA-MB231 cell | Running | Voluntary exercise; |
-Tumor growth | -Inhibiting the growth of carcinomas | 27 |
Chemical |
Female Balb/c | 7,12-dimethylbenzanthracene |
Swimming | physical training of |
-Gene expression | -Reduced Th1 cytokine |
28 |
ER: estrogen receptor, PR: progesterone receptor, HER2: receptor tyrosine-protein kinase erbB-2, PTEN: Phosphatase and tensin homolog, APOE: apolipoprotein E, FVB: Friend leukemia virus B, ANKRD1: Ankyrin repeat domain protein, CTGF: connective tissue growth factor, PI3K: phosphoinosidied 3-kinase, AKT: protein kinase B, ERK: extracellular signal regulated kinase, IL: interleukin, TNF-α: tumor necrosis factor – α, CRP : C-eactive protein, VEGF: vascular endothelial growth factor, HIF-1 α: hypoxia-inducible factor 1- α, CCL2: C-C motif chemokine ligand 2, CXCR4: C-XC chemokine receptor type 4, Ldha: lacate dehydrogenase A, HKII: hexokinase II, Glut 1: glucose transporter 1, Mtor : mammalian target of rapamycin, Lats2: large tumor suppressor kinase 2, CD8: cluster of differentiation 8, FoxP3: forkhead box P3, Gata3: GATA binding protein 3, Th : T helper cell, TPM1: tropomyosin alpha-1chain, PDCD4: programmed cell death protein
Modern people often suffer from various diseases, which leads to death. In particular, the four major chronic diseases leading to death have been reported as cancer, diabetes, cardiovascular, and chronic lung diseases. According to the Cancer Society report, the most common cancer among women worldwide is breast cancer
Standard treatment methods such as various anti-cancer drugs and surgery are being developed, and alternative medical technologies for incurable diseases are also in development. Currently, there are four main ways of cancer treatments: 1) surgery, 2) chemotherapy, 3) radiation therapy, and 4) hormone therapy.
Prophylactic surgery suppresses the cancer progression by performing a biopsy for the purpose of diagnosis through surgery or removing the benign tumor completely. Surgery also prevents the spread of cancer to other cells in the body and helps relieve symptoms. Chemotherapy refers to the use of therapeutic agents for regulating hyperproliferative cells. Radiation therapy kills cancer cells by directly irradiating them. Hormone therapy that suppresses estrogen action is also used as a cancer treatment method, as breast cancer is affected by estrogen levels, unlike other cancers.
Disease increase over the last two decades may be due to a more westernized lifestyle, which is accompanied by excessive nutrition and lack of exercise
Physical activities of Korean women are very low compared to women in other countries. Moreover, many women have adopted western food and a sedentary lifestyle, which has led to reduced voluntary exercise. The highest incidence of cancer among Korean women is breast cancer, and it has been suggested that breast cancer may be related to metabolic problems. Therefore, the effectiveness of exercise for the treatment or prevention of breast cancer should be investigated in future clinical studies.
An experimental laboratory animal is defined as an animal developed and improved for use in accordance with the purpose of test, diagnosis, education, research, and biological products in the research process. Among laboratory animals, primates such as
The breast cancer animal model consists of chemically induced models, transgenic mice models, orthotopic mice models, and xenograft models. In the case of chemically induced breast cancer models, 7,12-dimethylbenzanthracene (DMBA; 1 mg/mL weekly, for six weeks) is injected subcutaneously into the side of the abdomen. Poly-aromatic structure of lipophilic molecule, DMBA has high carcinogen activity in the breast. To evaluate tumor progression, mice are established with genetic modifications that target the oncogene, such as simian virus 40 (SV40) T antigens and polymer middle T antigen (PyMT). In the establishment of mice models by injection with breast cancer cells, mice are mainly used in the study of tumor biology and pharmacology, as these models retain the biological properties of cancer. Breast cancer cells are injected into the mammary fat pad of host mice to obtain orthotropic models. In this case, the number of cells used is appropriate (1 x 105 to 1 x 106/mouse), and cancer cells injected into the mouse organs exhibit properties similar to breast cancer generated in the human body over time, and can be correlated to metastatic cancer. To develop a xenograft model, cells (1 x 106 to 1 x 107/mouse) are injected subcutaneously into the dorsal side of the mouse.
Using these various animal models, studies on the beneficial effect of exercise against tumor growth and tumorigenesis of breast cancer have been extensively reported (
If so, which mechanism of exercise showed an anti-cancer effect? Results strongly suggest that exercise inhibits epigenetic modification of tumor cells, but enhances apoptosis and immune suppression
However, this claim raises further questions as to why exercise is closely related to change in the microenvironment of cancer. One possible belief is that exercise can exert anti-cancer effects by solving problems that arise during metabolic processes. During carcinogenesis, most tumor cells exert cell growth signaling pathway via glucose metabolic reprograming
However, the anti-cancer effects of KD and exercise can be contradictory. Acute exercise did not change tumor formation, but continuous steady aerobic exercise displayed effective anticancer effects. The general view presented in many studies is that exercise exerts an anti-cancer effect by reducing the size of tumors, promoting energy metabolism, and increasing immune activity by constant exercise. Therefore, further studies should investigate that find and apply an appropriate energy source for exercise that show anticancer efficacy.
Various preclinical studies have shown that exercise weakens tumor growth and tumor development. Moreover, these studies suggest that mice bearing breast cancer exhibited anti-cancer effects by increasing immune responses and anti-inflammatory factor levels through acclimation of increased exercise intensity every week. Thus, continuous exercise can have potential medical benefits as a prevention or therapeutic method for breast cancer. To facilitate this research, researchers need to study the etiological mechanisms that rely on clinical features with underlying pathological features of the disease, as well as based on mechanisms not necessarily present in patients. For example, using animal models to discover new treatments for a variety of diseases is an essential element in discovering new therapeutic targets and performing drug testing at the preclinical stage.
This research was supported by a grant from the Osong Medical Cluster R&D Project funded by the Republic of Korea’s Health and Welfare (grant number HO15C0001). This paper was supported by the KU Research Professor Program of Konkuk University.