by The University of Hong Kong

A) Trial schematic for establishing an HFD-fed NAFLD-breast cancer mice model. B, C) Mice on the HFD diet showed accelerated body weight growth (B) and higher body fat rates (C). D) Increased wet weights of adipose tissue were observed. E–H) Evaluation of NAFLD revealed that the HFD induced higher liver wet weight (E) and aberrant expression of liver enzymes (H). Lipid droplet accumulation in the liver tissue was detected by H&E (F) and oil red O (G) staining. I–L) For tumors, mice fed with HFD showed accelerated mammary tumor growth (I) and higher tumor wet weight (J). The expression levels of PCNA were confirmed by western blot (K) and quantified (L). Credit: Cell Death & Disease (2024). DOI: 10.1038/s41419-023-06386-8

A research team from the School of Chinese Medicine, LKS Faculty of Medicine, the University of Hong Kong (HKUMed) has made a remarkable discovery that patients with non-alcoholic fatty liver disease (commonly known as fatty liver disease) exhibit excessive production of a hepatokine called Fibroblast Growth Factor 21 (FGF21) in their liver, which may accelerate the growth of breast cancer tumors.

The findings provide scientific evidence validating the traditional Chinese medicine (TCM) theory of breast disease from liver dysfunction, and shedding light on the potential mechanisms underlying TCM treatments for breast-related conditions. The findings were published in the journal Cell Death and Disease.

Breast cancer is the most common cancer among women both in Hong Kong and worldwide. Ongoing research has revealed that breast cancer is a systemic disease, with its etiology and pathogenesis potentially linked to multiple organs and tissues.

The liver is a key organ that plays a central role in the body's energy metabolism, and the incidence of liver diseases, such as fatty liver, has increased rapidly in recent years. Clinical studies have found that fatty liver disease is an independent risk factor, contributing to an increased incidence of breast cancer.

Patients with fatty liver have about a 1.4-fold higher risk of developing breast cancer, and the condition also adversely affects the malignancy of breast cancer. However, the direct impact and underlying mechanism of fatty liver on breast cancer remain unclear.

The influence of the liver on breast cancer is often underestimated due to other surrogate diseases, such as obesity, diabetes and high blood pressure, in breast cancer patients.

FGF21 is a hepatokine, a protein secreted by the liver. Recent research has found that fatty liver and other liver diseases are often associated with the abnormal secretion of FGF21. This hormone can induce the development of various cancers, including liver, thyroid and lung cancer. However, the specific role of FGF21 in breast cancer has not been mentioned in previous research.

A research team led by Dr. Chen Jianping, Principal Lecturer in the School of Chinese Medicine, HKUMed, found that mice with fatty liver disease exhibited overexpression and secretion of the hepatokine FGF21 in the liver.

Dr Chen Jianping (left) provides scientific evidence for supporting the clinical application of the breast disease from liver dysfunction TCM theory. Credit: The University of Hong Kong

The team conducted an oncogenic activity study, which confirmed that excessive supplementation of exogenous FGF21 significantly accelerated the growth of mammary tumors in mice; while knockout of the FGF21 gene, in contrast, weakened the effect.

The in vitro cell model also revealed that liver cells in fatty liver could enhance the proliferation of breast cancer cells, but this effect was diminished when the FGF21 gene was removed from the liver cells. According to the mechanistic investigation, FGF21 can regulate signaling pathways related to the death of breast cancer cells, thereby promoting breast tumor growth.

The researchers also analyzed tumor samples from patients with primary breast cancer and found a higher expression of FGF21 than in normal breast tissue. The increased FGF21 expression was also associated with higher rates of recurrence and mortality in patients.

The study also found that excessive secretion of FGF21 by the liver in fatty liver disease could accelerate the growth of breast tumors, enhance the resistance of cancer cells to cell death, and reduce the therapeutic efficacy of the chemotherapy drug Doxorubicin.

Clinical studies have found that women with fatty liver disease have a significantly higher risk of breast cancer, highlighting the importance of liver health for the prevention of breast cancer in women and revealing the existence of the "liver-breast axis."

Dr. Chen pointed out that there is a TCM theory of "breast disease from liver dysfunction." She said, "This TCM theory emphasizes the critical role of liver health in maintaining women's breast health and the positive effect liver health has on the treatment of breast cancer.

"This study provides scientific evidence for the existence of a 'liver-breast axis' at both the animal and cellular levels, supporting the clinical application of the TCM theory of breast disease from liver dysfunction in breast cancer management."

Dr. Chen added that the team planned to build upon this study to further investigate the connection between the liver and the breast, with the aim of providing new insights and approaches that will advance understanding of the etiology and pathogenesis of breast cancer, as well as the development of novel clinical prevention and treatment of breast cancer.

More information: Yue Sui et al, Non-alcoholic fatty liver disease promotes breast cancer progression through upregulated hepatic fibroblast growth factor 21, Cell Death & Disease (2024). DOI: 10.1038/s41419-023-06386-8

Journal information: Cell Death and Disease 

Provided by The University of Hong Kong