ABSTRACT
The incidence of diabetes is markedly increasing worldwide. In addition to cardiovascular complications, many epidemiological studies have demonstrated that diabetic patients have a markedly increased risk of developing many types of cancer and several meta-analyses have found that metformin, the most commonly prescribed medication for type 2 diabetes, is associated with a lower risk of developing several cancers. Therefore, the suggested mechanism of metformin in the reduction of breast cancer will be discussed in this review.
KEYWORDS: AMPK pathway, breast cancer, diabetes, metformin
INTRODUCTION
Metformin, also known as 1, 1-dimethyl biguanide, has been used for many years, mostly to treat type 2 diabetes. Significant interest has been generated in repurposing metformin as an anticancer agent due to numerous studies conducted over the past 20 years that have associated the drug to lower rates of cancer incidence and death.[1]
Analysis of metformin for cancer prevention and treatment in persons with or without diabetes has generated a lot of interest and enthusiasm since an observational research conducted in Scotland in 2005. Many in vitro and in vivo investigations reported that metformin inhibits the growth of various cancer cell types, revealing an astounding decrease in cancer incidence and outcomes.[2] The following year, a population-based cohort study reported that type 2 diabetic patients taking metformin had a lower cancer-related mortality rate than those taking sulfonylureas. These findings were later confirmed by other researches in the early 2000s.[1]
The potential use of metformin in the prevention and treatment of breast cancer has been the subject of numerous investigations. A PubMed search for “breast cancer” AND metformin (December 29, 2023) found 837 publications, most of which were published in the last ten years. Given this context, the mechanism by which metformin reduces breast cancer will be covered in this review.
MECHANISM OF ACTION
Metformin can specifically lower cellular energy consumption by blocking respiratory complex I of the electron transport chain in the mitochondria, thus preventing protein synthesis and cell growth by activating AMPK and LKB1, which in turn inhibits the mammalian target of rapamycin (mTOR). It has also been suggested that metformin may work by interfering with hexokinases I and II, the enzyme that catalyzes the first step in glucose metabolism and upstream of AMPK activation. It has been demonstrated that the impact of metformin on cell metabolism causes apoptosis and subsequent cell death in tumor cells. Furthermore, without the aid of AMPK, metformin may work via the human epidermal growth factor receptor-2 (HER2). Metformin has been shown to inhibit HER2 tyrosine kinase activity and to stop the development of breast cancer cells that overexpress HER2. Lastly, research indicates that metformin may act indirectly on inflammation regulation and insulin sensitivity by blocking IL-6/JAK2/STAT3 signaling and other STAT3-related signaling pathways that are implicated in breast cancer. Metformin, however, lowers circulating insulin and insulin-like growth factor 1 (IGF-1), which is believed to raise the risk and accelerate the development of cancer. Therefore, metformin-induced whole-body improvements in insulin signaling may aid in the prevention and slowing of cancer.[1]
HOW DOES METFORMIN ACT IN THE REDUCTION OF BREAST CANCER?
A biological justification involving significant variables linked to the prognosis of breast cancer supports the antineoplastic effects of metformin in this disease. Metformin increases the uptake of glucose in skeletal muscle and inhibits the transcription of important gluconeogenesis genes in the liver. It reduces hyperinsulinemia caused by insulin resistance, enhances insulin sensitivity, and lowers blood glucose levels. Out of all the mechanisms, AMPK activation is the most important mechanism, which is the central cellular key energy sensor. This puts it in a unique position to ensure that cells have adequate metabolic resources before dividing, a process that consumes a lot of energy. Once activated, it inhibits several metabolic processes that favor catabolic processes (glycolysis, beta oxidation of fatty acids) and that significantly depend on a sufficient supply of cellular adenosine triphosphate (ATP) (gluconeogenesis, synthesis of proteins and fatty acids, biosynthesis of cholesterol). Furthermore, the AMPK pathway phosphorylates TSC2 and raptor to inhibit mTOR in two ways. Lower ATP levels activate AMPK, which phosphorylates TSC2 and increases its Rheb-GAP activity, thereby inhibiting the mTOR pathway and beneficial effects of growth factors or amino acids. Through raptor phosphorylation, metformin and its analogs also activate AMPK when TSC2 is not present. This effect seems to be directly related to mTOR kinase activity, potentially involving partial dissociation of PRAS40 and/or increased binding of 14-3-3 proteins.[3]
METFORMIN AND CANCER STEM CELLS
A subset of self-renewing cells called cancer stem cells (CSCs) is essential for the formation, development, and recurrence of tumors. Targeting CSCs with metformin has been the subject of numerous investigations due to their critical involvement in the whole spectrum of cancer. Zhu and associates demonstrated that metformin suppresses cancer stem cells using MMTV-ErbB2 transgenic mice, a model of HER2+ breast cancer. In this model, 10 weeks of premalignant metformin (250 mg/kg/day) reduced alveolar structures and lateral branching in comparison with controls. Moreover, the mammosphere-forming efficiency of mammary epithelial stem/progenitor cells isolated from metformin-treated animals was lower than that of controls due to the decline in the CD61high/CD49fhigh subpopulation. In a syngeneic graft mouse model, they demonstrated that pretreatment prevented the growth of tumors overexpressing ErbB2 and decreased downstream AKT signaling, ERK1/2 signaling, and phosphorylation of ErbB2 and EGFR.[1]
HOW METFORMIN MODULATES IMMUNITY?
The immune cells in the tumor microenvironment and/or mammary adipose tissue are altered by metformin, which can either prevent or treat breast cancer. One immune cell that is crucial to the development and spread of breast cancer is the macrophage. The two main polarized phenotypes of macrophages are M1 (which produces inflammation) and M2 (which can heal wounds and reduce inflammation). It is important to remember that polarization is a spectrum, with the two extremes being represented by the M1 and M2 phenotypes. Tumor-associated macrophages (TAMs) with an M2-like phenotype negatively impact the prognosis by using their capacity to remodel tissue to promote tumor growth and progression.
Obesity, a chronic, low-grade inflammatory state marked by an increase in adipose tissue macrophages and facilitating the establishment and/or progression of insulin resistance, is another risk factor for postmenopausal breast cancer. Moreover, adipose inflammation, which includes inflammation of the breast, is linked to an increased risk of breast cancer. In most adipose tissue depots, metformin reduces proinflammatory M1-like macrophages and increases M2-like macrophages, which promote insulin sensitivity. Jing et al. discovered that metformin lowers the serum levels of pro-inflammatory markers like TNF-α and IL-6 in mice fed a high-fat diet and used palmitate to stimulate RAW264.7 macrophages.[4]
EFFECTS OF METFORMIN IN PRECLINICAL STUDIES
Early studies demonstrated that metformin could limit the growth of cancer cell lines by inhibiting the cell cycle, as demonstrated by a significant reduction in the amount of cyclin D1 protein. Researchers examined the effects of metformin on a group of cell lines from breast, ovarian, and prostate cancer in vitro to assess the drug’s impact on cell proliferation. In MCF-7 human breast cancer cells, metformin functions as a growth inhibitor as opposed to an insulin sensitizer.
Additionally, they found that exposure to a concentration of a growth-inhibitory drug can cause decreased protein synthesis by activating the AMPK pathway and inhibiting mTOR, which stops both growth and proliferation.[3] The fact that metformin-induced AMPK stimulation completely prevents cell proliferation in ER-positive cell lines was validated by later studies on breast cancer cell lines by hormone receptor status. According to recent research, metformin specifically destroys the stem cells of breast cancer. Four distinct genetic subtypes of breast cancer cells were treated with metformin and doxorubicin. In a xenograft mouse model, this combination was more successful in reducing tumor mass, extending remission, and eliminating cancer and non-stem cells in culture. Clinical research was justified by these thorough preclinical results, which showed that metformin had anticancer effects in all subtypes of breast cancer as well as in models that were resistant to cytotoxic therapy.[5]
EFFECTS OF METFORMIN IN CLINICAL STUDIES
Prescribing metformin for both prevention and treatment of breast cancer has been prompted by the intriguing outcomes of metformin in preclinical and retrospective clinical studies. Numerous epidemiological study findings consistently showed that metformin-treated T2DM patients were less likely to develop different kinds of cancer than those on other antidiabetic drugs. This conclusion was corroborated by other meta-analyses that showed metformin reduces the risk of cancer by 30 to 50%. Several studies also evaluated how metformin affected the metabolic status of cancer patients with and without diabetes. Metformin was found to improve multiple metabolic parameters and reduce fasting insulin by 22% in women without diabetes who had early stage breast cancer. According to another study, women without diabetes who received metformin for breast cancer had fewer Ki67-positive cancer cells and different gene expression of markers related to the mTOR and AMPK pathways.[6]
CONCLUSION
Metformin is a frequently prescribed oral medication used as the first line of treatment for type 2 diabetes. The growth of cancer cell lines, including breast cancer, is inhibited in both in vitro and in vivo tumor models. According to both population and retrospective studies, metformin improves diabetic patient’s response to neoadjuvant chemotherapy while lowering cancer incidence and cancer-related mortality. Metformin causes AMPK activation, which lowers insulin levels and inhibits protein synthesis pathways, thereby reducing the growth and proliferation of cancer cells. It would be possible to identify more characteristics of tumors and patients who will benefit from this medication in future research.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
REFERENCES
- 1.E Stringer-Reasor EM, Elkhanany A, Khoury K, Simon MA, Newman LA. Disparities in breast cancer associated with African American identity. Am Soc Clin Oncol Educ Book. 2021;41:e29–46. doi: 10.1200/EDBK_319929. [DOI] [PubMed] [Google Scholar]
- 2.C. DeSantis, Surveillance and Health Services Research ACSEAG, J. Ma . Breast cancer statistics. CA Cancer J Clin. 2013;64:52–62. doi: 10.3322/caac.21203. [DOI] [PubMed] [Google Scholar]
- 3.Gant DMA, Parris AB, Yang X. Metformin-induced down regulation of c-Met is a determinant of sensitivity in MDA-MB-468 breast cancer cells. Biochem Biophys Res Commun. 2022;613:100–6. doi: 10.1016/j.bbrc.2022.04.139. [DOI] [PubMed] [Google Scholar]
- 4.Jing Y, Wu F, Li D, Yang L, Li Q, Li R. Metformin improves obesity-associated inflammation by altering macrophages polarization. Mol Cell Endocrinol. 2018;461:256–64. doi: 10.1016/j.mce.2017.09.025. [DOI] [PubMed] [Google Scholar]
- 5.Corleto KA, Strandmo JL, Giles ED. Metformin and breast cancer: Current findings and future perspectives from preclinical and clinical studies. Pharmaceuticals. 2024;17:396. doi: 10.3390/ph17030396. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Dietze EC, Sistrunk C, Miranda-Carboni G, O’Regan R, Seewaldt VL. Triple-negative breast cancer in African-American women: Disparities versus biology. Nat Rev Cancer. 2015;15:248–54. doi: 10.1038/nrc3896. [DOI] [PMC free article] [PubMed] [Google Scholar]
