Increased circulating resistin levels in early-onset breast cancer patients of normal body mass index correlate with lymph node negative involvement and longer disease free survival: a multi-center POSH cohort serum proteomics study

Abstract

BackgroundEarly-onset breast cancer (EOBC) affects about one in 300 women aged 40 years or younger and is associated with worse outcomes than later onset breast cancer. This study explored novel serum proteins as surrogate markers of prognosis in patients with EOBC.MethodsSerum samples from EOBC patients (stages 1–3) were analysed using agnostic high-precision quantitative proteomics. Patients received anthracycline-based chemotherapy. The discovery cohort (n = 399) either had more than 5-year disease-free survival (DFS) (good outcome group, n = 203) or DFS of less than 2 years (poor outcome group, n = 196). Expressed proteins were assessed for differential expression between the two groups. Bioinformatics pathway and network analysis in combination with literature research were used to determine clinically relevant proteins. ELISA analysis against an independent sample set from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort (n = 181) was used to validate expression levels of the selected target. Linear and generalized linear modelling was applied to determine the effect of target markers, body mass index (BMI), lymph node involvement (LN), oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 status on patients’ outcome.ResultsA total of 5346 unique proteins were analysed (peptide FDR p ≤ 0.05). Of these, 812 were differentially expressed in the good vs poor outcome groups and showed significant enrichment for the insulin signalling (p = 0.01) and the glycolysis/gluconeogenesis (p = 0.01) pathways. These proteins further correlated with interaction networks involving glucose and fatty acid metabolism. A consistent nodal protein to these metabolic networks was resistin (upregulated in the good outcome group, p = 0.009). ELISA validation demonstrated resistin to be upregulated in the good outcome group (p = 0.04), irrespective of BMI and ER status. LN involvement was the only covariate with a significant association with resistin measurements (p = 0.004). An ancillary in-silico observation was the induction of the inflammatory response, leucocyte infiltration, lymphocyte migration and recruitment of phagocytes (p < 0.0001, z-score > 2). Survival analysis showed that resistin overexpression was associated with improved DFS.ConclusionsHigher circulating resistin correlated with node-negative patients and longer DFS independent of BMI and ER status in women with EOBC. Overexpression of serum resistin in EOBC may be a surrogate indicator of improved prognosis.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0938-6) contains supplementary material, which is available to authorized users.

Adipocytes and Obesity-Related Conditions Jointly Promote Breast Cancer Cell Growth and Motility: Associations With CAP1 for Prognosis

“…Furthermore, resistin has been reported to be elevated in obese individuals and among breast cancer patients (not adjusted for BMI), although the results have been conflicting ( 11 – 14 ). While several studies have shown increased systemic and breast tumor resistin levels among postmenopausal breast cancer patients to be positively associated with increasing BMI, poor tumor characteristics and impaired prognosis, an inverse association was recently reported among early onset breast cancer patients, independent of BMI ( 13 , 35 , 36 ). In this cohort of chemotherapy-treated patients, aged 40 years or younger, higher circulating resistin levels were in contrast associated with lymph-node negative disease and longer disease-free survival ( 36 ).…”

Retracted: Resistin effects on pancreatic cancer progression and chemoresistance are mediated through its receptors CAP1 and TLR4

“…In an earlier report (Kuo et al, ), resistin was reported to induce EMT in lung cancer cells resulting in increased invasion and migration, thus confirming our observation that resistin has a profound effect on cancer cells’ proliferation, migration, and invasion. In addition, STAT3 has often been connected to the acquisition of chemoresistance (Bharti, Dey, & Mandal, ) and resistin itself is known to induce resistance to chemotherapy (Liu et al, ; Malvi et al, ; Zeidan et al, ). It was, therefore, logical to assess an effect of resistin on the sensitivity of pancreatic cancer cells to chemotherapy.…”

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

“…Leptin and resistin are well-known adipokines linked to breast cancer (51). Both are secreted primarily by adipose tissue, increase with higher degrees of adiposity, and has been implicated for their role in obesity, inflammation, and breast tumorigenesis (51)(52)(53). Breast cancer patients are characterized by high serum leptin concentrations as well as increased leptin receptor expression especially in higher pathological grade tumor tissues and patients who develop resistance to anti-cancer treatments (54,55).…”