Adipocytokines and breast cancer risk

INTRODUCTION

Breast With 1.38 million new cases identified and 458,000 fatalities in 2008, cancer is the commonly occurring malignancy among women and the leading cause of cancer-related death. (Jemal et al., 2011) breast cancer is the most frequent cancer worldwide. Breast cancer claimed the lives of over 508,000 women worldwide in 2011. Obesity, a global health problem in recent decades, resulted from diminished physical activity and eating habits in countries with affluence. In many developed countries, obesity affects more than one-fifth of the adult population, and In developing countries, the proportion is increasing. In developing countries, the ratio is rising. Obesity has been associated with an increased risk of breast cancer in postmenopausal women, and it is one of the frequent factors. (Ferlay et al., 2010)

.(Dual Effects of Weight and Weight Gain on Breast Cancer Risk – PubMed, n.d.) (Trentham-Dietz et al., 1997)

Obesity-related interventions are a great way to avoid breast cancer. Adiponectin is an essential adipokine that is considered one of the fundamental factors in obesity carcinogenesis and a vital connection for the obesity-breast cancer relationship.(Dalamaga, Diakopoulos, et al., 2012) Obesity is a growing public health issue for the last 30 years, and it now affects practically every country. Obesity which is a primary concern nowadays for the previous 30 years, is affecting almost every country. Obesity has been linked to diabetes, metabolic syndrome, cardiovascular disease, and cancer, to name a few, and a more considerable tumour burden and histopathological grade. (Somasundar et al., 2004)(Renehan et al., 2008) 

Mostly, postmenopausal women are overweight or obese is a significant risk factor for breast cancer. Breast cancer in postmenopausal women is increased by excess body weight by 30%–50%.(Dalamaga, Karmaniolas, et al., 2013a)(Dual Effects of Weight and Weight Gain on Breast Cancer Risk – PubMed, n.d.) 

How does obesity contribute to breast cancer?

Obesity and breast cancer are linked by complicated mechanisms that have yet to be fully comprehended. Several studies have connected abnormal levels of estrogen, insulin, or adipokines to an increased risk of breast cancer in obese women(Gunter et al., 2009). (Van Kruijsdijk et al., 2009), 

Adipose tissue may play a key role in carcinogenesis; According to a recent hypothesis, carcinogenesis is the cause of cancer. Adipose tissue was once assumed to be primarily helpful for fat storage and energy production. This tissue is now thought to be an endocrine organ that secretes several different adipokines. One of these adipokines, adiponectin, has been related to cancer. Adiponectin is a hormone that is thought to be protective because it is involved in the pathophysiology of atherosclerosis with anti-inflammatory activity and plays a significant role in glucose regulation with potent insulin-sensitizing activity affecting glucose uptake in (Waki et al., 2005) the muscle. It also plays a role in lipid homeostasis and plays a role in regulating glucose, with potent insulin-sensitizing activity affecting glucose uptake in the muscle.

Adipokines, which are tiny peptide hormones White adipose tissue adipocytes are the leading producers of growth factors. The majority of breast tissue consists of adipocytes (almost 90% of breast volume) and epithelial cells (the remaining 10%). Obese people have high levels of deleterious proinflammatory adipokines such as leptin, tumour necrosis factor (TNF), interleukin-6 (IL-6), interleukin-8 (IL-8), plasminogen activator inhibitor-1 (PAI-1), resistin, and hepatocyte growth factor (HGF) and low levels of beneficial adipokines such as adiponectin and visfatin. Obesity-related illness is hypothesized to be exacerbated by disturbance of the adipokine system. Adipokines’Adipokines’ potential role in the development of breast cancer has recently received a lot of attention. According to Vona-Davis et al., adipokines are also vital contributors to obesity-related breast cancer, and adiponectin levels are lower in breast cancer patients, according to a recent meta-analysis. (De Pergola & Silvestris, 2013)(Cao, 2014)(Rose et al., 2004)(Vona-Davis & Rose, 2007)(Macis et al., 2014)

There are more than twenty adipokines, Only twelve adipokines (adiponectin, leptin, IL-6, TNF-, HGF, PAI–1, resistin, secreted frizzled-related protein 5 (SFRP-5), lipocalin 2, IL-8, apelin, and visfatin) have been associated with breast cancer. To discover more about the link between obesity and the risk of breast cancer, visit the National Cancer Institute’sInstitute’s website. (Raucci et al., 2013).

Studies performed:

In a study chose one hundred nineteen data sets for meta-analysis after they had been assessed. A total of 3787 cases and 5231 controls were used to explore the association between adipokines and obesity in obese and non-obese people; 12,301 cases and 12,805 controls were utilized in studies examining the relationship between adipokines levels and breast cancer risk. Twenty-six studies revealed adipokine levels in obese and non-obese healthy adults (including 23 case-control studies and three cross-sectional studies). Several studies looked at the levels of adiponectin, leptin, IL-6, TNF-, resistin, visfatin, and PAI-1. Among the 93 investigations, 46 assessed leptin, 29 assessed adiponectin, 29 estimated IL-6 levels, 17 assessed TNF-, six assessed resistins, and three assessed HGF, PAI-1, and visfatin (including 85 case-control studies, two cross-sectional studies, and six cohort studies) reporting levels of adipokines among patients with breast cancer. BMI, adiponectin, leptin, resistin, and visfatin were the critical adjustments in each study. All of the studies have a quality score of at least 6.

Adipokines mechanisms and breast cancer:

Obesity and PBC are linked in some ways. However, the exact mechanism is unknown. Adipose tissue is the primary site for peripheral aromatization of androgens to estrogens after menopause, which can cause mitogenic activity in mammary epithelial cells. (Dalamaga, Diakopoulos, et al., 2012)(Type 2 Diabetes and Obesity Metabolic Interactions: Common Factor…: Ingenta Connect, n.d.) 

Extra adiposity is associated with high estrogen ranges. Obese postmenopausal ladies with BC present significantly better general and loose estradiol degrees in addition to elevated neighbourhood estrogen tiers inside breast tumours in comparison to wholesome girls (Wysocki & Wierusz-Wysocka, 2014)(Lorincz & Sukumar, 2006)

Hyperinsulinemia, insulin resistance, and dyslipidemia can also be caused by increased adiposity, mainly increased visceral fat. Hyperinsulinemia, on the other hand, causes higher levels of insulin-like growth factor I (IGF-I), which has a mitogenic effect on both normal and cancerous breast epithelial cells, as well as lowers hepatic synthesis of intercourse hormone binding globulin, resulting in a higher bioavailable fraction of both estradiol and testosterone. (Dalamaga, Diakopoulos, et al., 2012) (Type 2 Diabetes and Obesity Metabolic Interactions: Common Factor…: Ingenta Connect, n.d.)

.Insulin resistance, type 2 diabetes (t2DM) and metabolic syndrome have all been linked to an increased risk of breast cancer in premenopausal and postmenopausal women.

Obesity-related insulin resistance and cancer are linked to a subclinical chronic low-grade inflammatory and prothrombotic state (Dalamaga, Diakopoulos, et al., 2012) (Doyle et al., 2012). The activation of proinflammatory adipocytokines and the repression of anti-inflammatory adipocytokines such as adiponectin boost hepatic production of acute-phase reactants, generating a positive feedback loop and promoting cancerogenesis.

Adipokine and Breast cancer:

Along with its storage function, , adipose tissue is an active endocrine organ that secretes various bioactive adipocytokines and inflammatory cytokines that regulate physiological and pathological processes such as appetite, insulin sensitivity, and resistance hematopoiesisnflammation, immunity, and angiogenesis. Innate and acquired immune activation, and growth factors and exposure to protumorigenic adipokines, as well as increased substrate availability to neoplastic breast cells are among the mechanisms linking excess adiposity in overweight/obesity patients with molecular and cellular pathways critical for carcinogenesis. The central part of breast tissues consists of adipocytes, with epithelial cells accounting for only 10% of the total volume. Together with their autocrine, paracrine, and endocrine functions, Adipocytes are thought to play a vital role in breast tumorigenesis. Deregulated adipokine expression could play a role in the obesity-BC connection. Although the precise interaction of adipokines has yet to be determined (Lorincz & Sukumar, 2006)(Dalamaga, Diakopoulos, et al., 2012) 

Leptin:

Leptin is a pleiotropic adipokine that affects food intake, energy expenditure, immunity, inflammation, hematopoiesis, cell differentiation, and proliferation. It is a 167-amino-acid peptide that is generated mainly in adipose tissue. Circulating leptin is related to body fat and swings in response to sudden changes in caloric intake, reflecting the amount of energy stored in adipose tissue. (Dalamaga, Chou, et al., 2013)

Normal breast epithelium, BC cell lines, and solid malignancies all expressed leptin gene expression leptin was shown to be overexpressed in the vast majority of instances of breast carcinoma(Lorincz & Sukumar, 2006) A increasing body of evidence suggests that leptin has two pathways for its BC neoplastic actions. (HS et al., 2013) To begin with, leptin may act directly on BC cells by activating receptor-mediated signalling pathways that promote tumour cell proliferation, migration, and invasion. In vitro studies have recently revealed that leptin plays a role in mammary tumorigenesis by stimulating tumour growth, cell survival, and transformation, amplifying ER signalling, which is vital for hormone-dependent BC growth and progression upregulating aromatase transcription, which leads to increased oestrogen synthesis. Leptin, via its receptor LepR, may enhance BC cell growth and proliferation by activating a variety of growth and survival signalling pathways, including the canonical (S et al., 2011)(Ray, 2012)

Adiponectin is a 244-amino-acid, 30-kDa protein released primarily by white adipose tissue and shares similarities with collagen VIII, X, complement factor C1q, and tumour necrosis factor (TNF-)(Dalamaga, Diakopoulos, et al., 2012). Hypoadiponectinemia is the common pathodenominator of metabolic syndrome, including hypertension, dyslipidemia, obesity, hyperglycemia, and insulin resistance. Furthermore, in vivo hypoadiponectinemia has recently been negatively correlated with insulin resistance and obesity-related malignancies, such as BC, colon cancer, renal cancer, certain myeloid hematologic malignancies, and gastric and prostate cancer(Dalamaga, Diakopoulos, et al., 2012).

Resistin:

Resistin, also known as a fatty tissue-specific secretory factor or inflammatory zone 3, is a 12-kDa cysteine-rich polypeptide that belongs to the resistin-like molecules, a small family secreted proteins characterized by the unique spacing difference of 10-11 cysteine residues.

Human resistin is generated in cells other than adipocytes, primarily macrophages and monocytes, especially in visceral adipose tissue, which has a high metabolic turnover(DR & MA, 2011)

Hyperrestinemia in vivo is connected to the risk of BC, particularly in postmenopausal women, according to the bulk of epidemiologic research looking into the link between serum resistin and BC (Dalamaga, Karmaniolas, et al., 2013b)(Dalamaga et al., 2013) 

In univariate and multivariable analyses adjusting for age, date of diagnosis, family history of cancer, alcohol consumption, smoking status, physical activity, and other factors, our group found that mean serum resistin levels were significantly higher in postmenopausal women suffering from BC than in age-matched control participants and women with benign breast lesions.

Nampt:

Visfatin, also known as nicotinamide phosphoribosyl-transferase (Nampt) or pre-B cell colony-enhancing factor, is a novel pleiotropic adipokine found in visceral fat that acts as an adipocytokine, a growth factor, and an enzyme. It is involved in various metabolic and stress responses and cellular energy metabolism, particularly nicotinamide Serum Nampt concentrations are higher in obese women, obese children and adolescents, and patients with metabolic syndrome, type 2 diabetes non-alcoholic fatty liver disease, and coronary heart disease. (A et al., 2008)(Dalamaga et al., 2011)(LQ et al., 2011) 

Nampt expression is upregulated in primary colorectal cancer and prostate cancer, both linked to obesity and overweight. Surprisingly, serum Nampt levels are considerably higher in individuals with Postmenopause(PBC). They suggested that it could be a viable biomarker for BC. (Dalamaga, Archondakis, et al., 2012). PBC patients mean serum Nampt was considerably greater than healthy controls and women with benign breast tumours of similar age.

Future opportunities:

Obesity, its metabolic consequences, and breast cancer have all become global severe health concerns. Obesity raises the risk of developing cancer and dying (Pichard et al., 2008)(Lorincz & Sukumar, 2006). Obesity and BC, particularly in Unbalanced expressiveness in postmenopausal women, may be connected. Of adipokines, While researching the connection between adipokines and BC may lead to potential preventive and treatment options and altering one’sone’s lifestyle, are still available. The essential factor in preventing PBC caused by fat. Adipokines modulation, particularly in women who are overweight or obese, may be a particularly enticing target for BC prevention. A wide range of behavioural and pharmacological treatments are available. They have been linked to improved modulation of the major.