Serum resistin is inversely related to breast cancer risk in premenopausal women

Highlights

• Resistin levels significantly differ in patients with ductal breast carcinoma.

• Serum resistin is inversely related to breast cancer risk in premenopausal women.

• A protective role of resistin against BC development is suggested.

Abstract

Background

Adipokines have been suggested as potential mediators linking obesity and breast cancer. Resistin is the least-studied adipokine with diverse findings regarding its association with disease development and progression. The present study aimed to determine resistin serum levels in breast cancer in relation to the histological type of disease and to investigate their association with breast cancer risk.

Methods

The study included 216 women, of which 163 were diagnosed with breast cancer (58 with IDC, 52 with DCIS and 53 with LN) and 53 were healthy. Serum levels of resistin, leptin and adiponectin were quantitatively determined in duplicates by ELISA. Differences in resistin levels among patient groups were evaluated with Kruskal–Wallis and Mann–Whitney tests. The association of resistin with breast cancer risk was evaluated by multiple logistic regression analysis.

Results

Resistin levels varied between histological types of breast cancer (p = 0.044). Significant differences in serum resistin were observed in IDC patients compared to those with DCIS and to controls (p < 0.014 and p < 0.03, respectively). Decreased levels of resistin, adiponectin and leptin were observed in premenopausal patients. Resistin was associated with a reduced risk for ductal carcinoma only in premenopausal women (OR: 0.364, 95% CI: 0.154–0.862, p < 0.022).

Conclusion

Our findings indicate that resistin levels were inversely related to breast cancer risk in premenopausal women, supporting a protective role of resistin for these patients. Further advances in adipokine research may lead to tangible benefits for overweight/obese women at an increased risk for breast cancer.

Introduction

Worldwide, breast cancer (BC) is the most frequently diagnosed cancer and the second cause of cancer-related death in women [1]. As its prevalence increases with age, BC is more common in older postmenopausal women. During the last decades, BC incidence rates have been rising dramatically primarily due to the prolonged life-span and the increased exposure to well-established risk factors. These include age and reproductive factors such as earlier age at menarche, later age at menopause, older age at first birth, decreased parity, and use of hormone replacement therapy or oral contraceptives [2], [3]. Histological characteristics, notably atypical hyperplasia of the mammary gland and carcinoma in situ as well as high breast density on mammographic screening have been associated with an increased risk of BC [4]. Among lifestyle habits, alcohol consumption has been moderately related to BC development [2], [3]. Obesity is considered an important risk factor of BC, particularly in postmenopausal women [2], [5]. Other common risk factors for BC include the presence of germline mutations in BRCA1 or 2 genes and a family history of BC [2], [4]. Despite the identification of numerous factors that are associated with BC risk, it is interesting that more than 50% of BC cases appear to arise in the absence of known risk factors [6].

Obesity has been recognized as a major public health issue in industrialized countries that is growing rapidly and affects a significant part of the population across all age, gender and ethnic groups. It is well-established that obesity increases the risk for various types of cancer including colon, prostate and breast [7], [8], [9]. Many studies have provided strong evidence that obesity is associated with BC primarily in the postmenopausal population, even though the underlying mechanisms remain largely unclear [8], [9], [10]. It has actually been reported that excess body weight significantly increases postmenopausal BC risk by 30–50% [11]. Obesity has also been associated with characteristics of a more aggressive BC phenotype such as increased tumor burden, higher histopathological grade and high incidence of lymph node metastasis [12], [13], [14]. In addition, there is evidence that overweight/obese patients present poorer outcomes, being at an increased risk for BC progression and BC-related mortality regardless of their menopausal status [5], [14], [15].

Recently, adipokines have been suggested as potential mediators linking obesity and BC by several experimental and epidemiological studies [6], [12], [16], [17], [18], [19], [20], [21], [22], [23], [24]. The adipose tissue is nowadays considered not only a fat-storing tissue but also an endocrine organ secreting various adipokines. Adipokines are a group of biologically active polypeptides mainly produced by adipose tissue and released in the systemic circulation. They can act on target tissues by autocrine, paracrine or endocrine mechanisms and have been proposed to influence both BC risk and biological behavior [24], [25]. However, their role and associated mechanisms mediating the effect of obesity on BC development and progression in pre- and postmenopausal women need to be further elucidated.

Resistin, also known as adipocyte-secreted factor or found in inflammatory zone 3 (FIZZ3), is a novel adipokine involved in the regulation of insulin resistance [26], [27]. It is a 12.5 kDa hormone encoded by the RSTN gene and a member of the newly discovered family of cysteine-rich proteins called “resistin-like molecules” (RELMs) [27], [28], [29]. Although resistin was originally described as an adipocyte-derived cytokine in rodents, it is mostly expressed by macrophages in humans [30]. Up-regulation of resistin has been observed in obesity while its levels have been associated with inflammatory markers, suggesting its implication in obesity-related pathologic conditions accompanied by chronic inflammation [31]. Thus, resistin has been proposed as a potential link between obesity and atherosclerosis, cardiovascular diseases, rheumatic diseases, non-alcoholic fatty liver disease and various malignancies [31]. Recent studies have demonstrated that circulating resistin levels are significantly elevated in patients with breast, gastric, colorectal and endometrial cancer as well as with esophageal squamous cell carcinoma and lymphoma [32], [33], [34], [35], [36], [37], [38], [39], [40], [41].

Until today, an exceptionally limited number of studies have examined the association between resistin expression and BC with diverse findings. Moreover, most reports have investigated resistin in postmenopausal individuals while very few data are currently available on its role in premenopausal BC. The wide range and inconsistency between findings can be partly attributed to inhomogeneity of study design, differences in detection methods and small sample sizes resulting in limited power to detect small differences in resistin levels. Better-controlled studies, accounting for potential confounders using appropriate statistical models, are needed to unequivocally establish whether resistin is associated with BC pathogenesis in the pre- and postmenopausal population.

In the present study, we investigated serum resistin in patients with newly diagnosed BC compared to healthy controls. Resistin levels were analyzed in relation to the histopathological type of the disease, in three distinct groups of patients with invasive ductal carcinoma (IDC), in situ ductal carcinoma (DCIS) and lobular neoplasia (LN). Logistic regression analysis was applied to assess the potential association between serum resistin levels and BC risk in pre- and postmenopausal women.