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The Lancet Oncology

Monday, June 22, 2009

Lipocalin 2 promotes breast cancer progression: Breast Cancer Biomarker Highlighted as useful in Non-Invasive Diagnostic Assays

Lipocalin-2 (lcn2) a 25 kDa secretory glycoprotein, also called NGAL (neutrophil gelatinase-associated lipocalin) is predominantly expressed in adipose tissue and liver and belongs to the lipocalin superfamily that consists of over 20 small secretory proteins. Lipocalin folds consist of 8 antiparallel ß-sheets that surround a hydrophobic pocket. A common feature of this protein family, following from its structure, is its capacity to bind and transport small lipophilic substancies such as free fatty acids, retinoids, arachidonic acid and various steroids.

Although Lipocalin-2 was identified more than a decade ago, the physiologic function of this protein remained poorly understood. Research now showd that lipocalin-2 appears to be upregulated in cells under the “stress” (e.g. from infection, inflammation, in tissues undergoing involution to ischemia or neoplastic transformation).

Therapeutic importance
Plasma levels of lipocalin-2 rise in inflammatory or infective condition. The protein mediates an immune response to bacterial infection by sequestering iron. Therfore, Lipocalin-2 may represent a promising candidate as a therapeutic agent against bacterial infection.
Several recent reports suggest that lipocalin-2 may also represent a sensitive biomarker for early renal injury. In cardiopulmonary bypass-induced acute renal injury and cisplatin-induced nephrotoxic injury, increased de novo synthesis of lipocalin-2 in proximal tubule cells leads to sharply increased concentration of this protein in both urine and serum.

Lipocalin-2 is also highly expressed after malignant transformation of the lung, colon and pancreatic epithelia. Circulating levels of lipocalin-2 play a causative role in pathogenesis of obesity-induced metabolic disorders such as insulin resistance, Type 2 Diabetes Mellitus and cardiovascular disorders. In addition, serum lipocalin-2 concentrations were positively associated with adipocyte-fatty acid binding protein (A-FABP), a novel serum marker for adiposity and metabolic syndrome.

Role in Breast Cancer
Reserach show that lipocalin-2 plays an important role in breast cancer, in complex with matrix metalloproteinase-9 or MMP-9, by protecting MMP-9 from degradation thereby enhancing its enzymatic activity and facilitating angiogenesis and tumor growth.

Researchers demonstrated that the binding of neutrophil gelatinase-associated lipocalin (NGAL) to matrix metalloproteinase-9 (MMP-9) protects the extracellular matrix remodeling enzyme from autodegradation. Although breast cancer cells express MMP-9 and not the NGAL protein, clinical researchers hypothesized that the addition of NGAL to breast cancer cells, result in a more aggressive phenotype in vivo. Based on previous reports that MMPs can be detected in the urine of cancer patients, researchers wondered whether MMP-9/NGAL could be detected in the urine of breast cancer patients and whether it might be predictive of disease status.

In an article by Yang, Bielenberg, Rodig and colleagues published in the Proceedings of the National Academy of Sciences (PNAS) investigating the function of lipocalin 2 in breast cancer progression, the research team identified the mechanisms in which lipocalin 2 promotes breast cancer progression.

Yang and colleagues noted that lipocalin-2 levels were consistently associated with invasive breast cancer in human tissue and urine samples. In research designed to unravel the role of Lipocalin 2 was overexpressed in human breast cancer cells and was found to up-regulate mesenchymal markers, including vimentin and fibronectin, down-regulate the epithelial marker E-cadherin, and significantly increase cell motility and invasiveness.

These changes in marker expression and cell motility are hallmarks of an epithelial to mesenchymal transition (EMT). Reserachers also noted that Lcn2 silencing in aggressive breast cancer cells inhibited cell migration and the mesenchymal phenotype. Furthermore, reduced expression of estrogen receptor (ER) α and increased expression of the key EMT transcription factor Slug were observed with lipocalin-2 expression.

Overexpression of ERα in Lcn2-expressing cells reversed the EMT and reduced Slug expression, suggesting that ERα negatively regulates Lcn2-induced EMT. Finally, orthotopic studies demonstrated that Lcn2-expressing breast tumors displayed a poorly differentiated phenotype and showed increased local tumor invasion and lymph node metastasis.

A non-invasive biomarker for advanced breast cancer
In this research, Yang demonstrated that lipocalin 2 promotes breast cancer progression by inducing the epithelial to mesenchymal transition (EMT), one of the key processes involved in tumor progression and metastasis. The team further showed that lipocalin-2 levels can be measured in urine samples, and high levels are correlated with cancer cell migration and invasiveness in women with advanced or metastatic estrogen-receptor (ER)-negative breast cancer.

These findings suggest the potential for lipocalin 2 as a non-invasive biomarker for advanced breast cancer. lipocalin-2, along with other urine biomarkers for various cancers discovered at Children’s Hospital Boston, is exclusively licensed to Predictive Biosciences for diagnostic assay development. Predictive Biosciences is an emerging molecular diagnostics company developing non-invasive diagnostic products for informed cancer management™.

"Estrogen-receptor negative breast tumors are among the most difficult to treat," said Marsha A. Moses, Ph.D., Professor of Surgery at Harvard Medical School and interim Director of the Vascular Biology Program at Children’s Hospital Boston, and co-author of the PNAS publication. Dr. Moses, a co-founder of Predictive Biosciences / , added, "We are excited by this research showing a strong correlation between high levels of Lcn2 and the aggressiveness of breast cancer. These studies suggest the potential for a simple, urine-based assay to measure Lcn2 as a way of monitoring cancer development and progression on an individual basis, and to determine if more aggressive treatment is needed. This would be an important step towards more accurate and personal cancer management for these patients."

Utilizing its portfolio of patented biomarkers and proprietary clinical approaches (such as Clinical Intervention Determining Diagnostic™ or CIDD); Predictive Biosciences is developing novel diagnostic assays that have exceptionally high negative predictive value (NPV) and positive predictive value (PPV) for cancer development and progression. This information, incorporated into current standard clinical practice, should lead to more effective utilization of existing tools and ultimately better outcomes for patients. Predictive aims to deliver highly accurate, convenient diagnostics to provide physicians with actionable information for personalized diagnostic follow-up and treatment plans – avoiding expensive, invasive procedures and increasing patient compliance and comfort.

"We are very pleased to be collaborating with Professor Marsha Moses and Children’s Hospital Boston on developing a number of urine-based cancer diagnostic assays," said Peter Klemm, Ph.D., President and Chief Executive Officer of Predictive.

"Already, Predictive is advancing novel bladder cancer assays, with plans to commercialize these tests via our CLIA lab. In addition, we have a rich pipeline of biomarkers poised for diagnostic assay development, including this very compelling breast cancer biomarker, Lcn2. Leveraging our deep clinical development and scientific capabilities, we are building a robust portfolio of innovative cancer assays, in collaboration with others who share our interest in delivering highly accurate and convenient cancer diagnostics for informed cancer management™."

For more information also read these PubMed abstracts:

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