Neutrophil Gelatinase-Associated Lipocalin (NGAL) Predicts Response to Neoadjuvant Chemotherapy and Clinical Outcome in Primary Human Breast Cancer

Abstract

In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC.

Iron and cancer: more ore to be mined

“…In mouse models of colorectal cancer, LCN2 expression was associated with reduced metastasis 45 although, paradoxically, it was also associated with the decreased overall survival of patients with colorectal cancer 46 . Nevertheless, recent results suggest that LCN2 expression is associated with shorter disease-free survival 47 and is an independent prognostic factor for decreased disease-free survival in primary human breast cancer 48 ; LCN2 is also associated with a poor prognosis in hepatocellular carcinoma 36 .…”

Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

“…In addition, the tumor microenvironment may alter NF-kappaB activity [66]. Many transcription factors, including the estrogen and androgen receptors, regulate NGAL expression by both positive and negative mechanisms [67][68][69][70][71][72][73][74][75][76][77]. 11 NGAL is an important molecule in many different types of cancer including: breast [9,10,77], colorectal (CRC) [78,79], endometrial [80], esophageal [7,81], gastric cancer [6], liver [82][83][84], lung [85][86][87] ovarian [88], pancreatic [89,90], prostate [76,91], renal [8,92] and thyroid cancer [68].…”

“…NGAL has also been observed in breast and other cancers and may be a predictor of poor patient survival and response to chemotherapy [72][73][74]94,96,97,105]. Breast cancer progression has been shown to be promoted by NGAL [96].…”

Lipocalin 2 promotes the migration and invasion of esophageal squamous cell carcinoma cells through a novel positive feedback loop

“…LCN2, a small molecular weight secreted glycoprotein, is up-regulated in a variety of cancers, including ESCC [8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Recent studies suggest LCN2 is a key player in different cancer types [10,12,23].…”

“…Furthermore, LCN2 can tightly bind to bacterial siderophore through a cell surface receptor, possibly serving as a potent bacteriostatic agent by sequestering iron, regulating innate immunity and protecting kidney epithelial cells from ischemia-reperfusion injury [5][6][7]. Elevated LCN2 has also been observed in a wide spectrum of solid tumor cells, including breast [8][9], colorectal [10][11], pancreatic [12], ovarian [13], thyroid [14], bladder [15], kidney [16] and gastric cancers [17], and gliomas [18], as well as esophageal squamous cell carcinomas (ESCC) [19][20][21]. We previously found that LCN2 is overexpressed in gastric carcinoma and its induction by 12-o-tetradecanoylphorbol-13-acetate (TPA) is controlled by CCAAT/enhancer-binding protein beta (C/EBPβ) [17].…”