Reliance on glycolysis for energy production is considered a hallmark of cancer and the glycolytic enzyme a-enolase is overexpressed in a range of cancer types. However, recent studies have revealed that a-enolase is involved in a variety of unrelated physiological processes and can be found in multiple unexpected cellular locations. This review focuses on the unlikely role of a-enolase as an extracellular plasminogen-binding receptor localised to the plasma membrane. Conversion of plasminogen to plasmin on the surface of cancer cells enhances their ability to invade through stroma by activating collagenases and degrading fibrin as well as extracellular matrix proteins. Increased expression of a-enolase is associated with increased migration and invasion of cancer cells, and decreased metastasis-free survival in patients with several cancer types, including non-small cell lung, pancreatic, breast and colorectal cancers. Due to its overexpression in a range of cancer types and multi-functional roles in key areas of tumour metabolism and metastasis, a-enolase may be useful as a universal cancer prognostic biomarker or therapeutic target.
Brain and Acute Leukemia, Cytoplasmic (BAALC) is a protein that controls leukemia cell proliferation, differentiation, and survival and is overexpressed in several cancer types. The gene is located in the chromosomal region 8q22.3, an area commonly amplified in breast cancer and associated with poor prognosis. However, the expression and potential role of BAALC in breast cancer has not widely been examined. This study investigates BAALC expression in human breast cancers with the aim of determining if it plays a role in the pathogenesis of the disease. BAALC protein expression was examined by immunohistochemistry in breast cancer, and matched lymph node and normal breast tissue samples. The effect of gene expression on overall survival (OS), disease-free and distant metastasis free survival (DMFS) was assessed in silico using the Kaplan-Meier Plotter (n=3,935), the TCGA invasive breast carcinoma (n=960) and GOBO (n=821) data sets. Functional effects of BAALC expression on breast cancer proliferation, migration and invasion were determined in vitro. We demonstrate herein that BAALC expression is progressively increased in primary and breast cancer metastases when compared to normal breast tissue. Increased BAALC mRNA is associated with a reduction in DMFS and disease-free survival, but not OS, in breast cancer patients, even when corrected for tumor grade. We show that overexpression of BAALC in MCF-7 breast cancer cells increases the proliferation, anchorage-independent growth, invasion, and migration capacity of these cells. Conversely, siRNA knockdown of BAALC expression in Hs578T breast cancer cells decreases proliferation, invasion and migration. We identify that this BAALC associated migration and invasion is mediated by focal adhesion kinase (FAK)-dependent signaling and is accompanied by an increase in matrix metalloproteinase (MMP)-9 but not MMP-2 activity in vitro. Our data demonstrate a novel function for BAALC in the control of breast cancer metastasis, offering a potential target for the generation of anti-cancer drugs to prevent breast cancer metastasis.
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