HER2/HER3 regulates lactate secretion and expression of lactate receptor mRNA through the MAP3K4 associated protein GIT1

One of the major features of cancer is Otto Warburg's observation that many tumors have increased extracellular acidification compared to healthy tissues. Since Warburg's observation, the importance of extracellular acidification in cancer is now considered a hallmark of cancer. Human MAP3K4 functions upstream of the p38 and JNK mitogen activated protein kinases (MAPKs). Additionally, MAP3K4 is required for cell migration and extracellular acidification of breast cancer cells in response to HER2/HER3 signaling. Here, we demonstrate that GIT1 interacts with MAP3K4 by immunoprecipitation, while cellular lactate production and the capacity of MCF-7 cells for anchorage independent growth in soft agar were dependent on GIT1. Additionally, we show that activation of HER2/HER3 signaling leads to reduced expression of lactate receptor (GPR81) mRNA and that both, GIT1 and MAP3K4, are necessary for constitutive expression of GPR81 mRNA. Our study suggests that targeting downstream proteins in the HER2/HER3-induced extracellular lactate signaling pathway may be a way to inhibit the Warburg Effect to disrupt tumor growth.NIEHS Training grant [ES007091]; Arizona Science Foundation [CAA 0226-08, ES006694, ES012007, ES04940]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Cloning, overexpression, purification, crystallization and preliminary X-ray analysis of a female-specific lipocalin (FLP) expressed in the lacrimal glands of Syrian hamsters

A female-specific lacrimal protein from Syrian hamsters has been crystallized by the sitting-drop vapour-diffusion method. The crystals belonged to space group P212121 and diffraction data were collected to 1.86 Å resolution

Fragile Histidine Triad Protein, Ww Domain-Containing Oxidoreductase Protein Wwox, And Activator Protein 2 Gamma Expression Levels Correlate With Basal Phenotype In Breast Cancer

BACKGROUND: The expression of fragile histidine triad protein (Fhit) and WW domain-containing oxidor-eductase protein (Wwox), tumor suppressors that are encoded by fragile (FRA) loci FRA3B and FPA16D, are lost concordantly in breast cancers. In the current study, the authors examined correlations among Fhit, Wwox, the activator protein 2 transcription factors AP2 alpha and AP2 gamma, cytokeratins 5 and 6 (CKS/6), epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) and their associations with breast cancer phenotypes. METHODS: Tissue microarrays constructed from 837 breast cancer blocks were immunostained. Expression in >10% of tumor cells was considered positive for cytoplasmic CKS/6, membranous EGFR, and nuclear AP2 alpha and AP2 gamma. Cytoplasmic Fhit and Wwox staining was scored according to staining intensity. ER, PR, and HER-2 status of tumors was derived from records. Correlations among immunohistochemical markers and tumor subtypes were assessed by univariate and multivariate statistical methods. RESULTS: Triple-negative tumors had more frequent expression of EGFR, CKS/6 (P < .001), and AP2 gamma (P = .003) and more frequent loss of Fhit and Wwox (P < .001), and an inverse correlation was observed between Fhit, Wwox expression and EGFR, ER, and PR expression (P < .001). Reduced Fhit expression was more common in HER-2-positive and AP2 gamma-positive cases (P < .001 and P = .002, respectively). There was a direct correlation noted between Fhit and Wwox (P < .001) and a borderline positive relation between AP2 alpha and AP2 gamma (P = .054). CONCLUSIONS: The results from this investigation suggested that reduced expression levels of Fhit, Wwox, and nuclear AP2 gamma have roles in the pathogenesis of basal-like differentiation in breast cancer. Alteration in the expression of fragile site genes occurs in most of these cancers and may contribute to defects in DNA repair, as observed in breast cancer 1 (BRCA1)-deficient cancers. Thus, DNA damage response checkpoint proteins may be targets for treatment. Cancer 2009;115:899-908. (c) 2009 American Cancer Society.Wo