Expression levels of the putative zinc transporter LIV‐1 are associated with a better outcome of breast cancer patients

Kasper, Grit; Weiser, Armin A.; Rump, Andreas; Sparbier, Katrin; Dahl, Edgar; Hartmann, Arndt; Wild, Peter J.; Schwidetzky, Uta; Castaños‐Vélez, Esmeralda; Lehmann, Kerstin

doi:10.1002/ijc.21235

Cited by 74 publications

(83 citation statements)

References 43 publications

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“…LIV-1 has been demonstrated to be correlated positively with ER expression and negatively with histological grade . Corroborating the data presented here, LIV-1 has also been demonstrated to predict longer relapse-free survival and OS in ER þ breast cancer (Kasper et al, 2005). The same study indicated that the predictive value of LIV-1 is dependent on other prognostic markers.…”

Section: Discussionsupporting

confidence: 82%

Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease

et al. 2008

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Gains of chromosomes 7p and 8q are associated with poor prognosis among oestrogen receptor-positive (ER þ ) stage I/II breast cancer. To identify transcriptional changes associated with this breast cancer subtype, we applied suppression subtractive hybridisation method to analyse differentially expressed genes among six breast tumours with and without chromosomal 7p and 8q gains. Identified mRNAs were validated by real-time RT -PCR in tissue samples obtained from 186 patients with stage I/II breast cancer. Advanced statistical methods were applied to identify associations of mRNA expression with distant metastasis-free survival (DMFS). mRNA expression of the key enzyme of cholesterol biosynthesis, squalene epoxidase (SQLE, chromosomal location 8q24.1), was associated with ER þ 7p þ /8q þ breast cancer. Distant metastasis-free survival in stage I/II breast cancer cases was significantly inversely related to SQLE mRNA in multivariate Cox analysis (Po0.001) in two independent patient cohorts of 160 patients each. The clinically favourable group associated with a low SQLE mRNA expression could be further divided by mRNA expression levels of the oestrogen-regulated zinc transporter LIV-1. The data strongly support that SQLE mRNA expression might indicate high-risk ER þ stage I/II breast cancers. Further studies on tumour tissue from standardised treated patients, for example with tamoxifen, may validate the role of SQLE as a novel diagnostic parameter for ER þ early stage breast cancers.

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Section: Discussionsupporting

confidence: 82%

Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease

et al. 2008

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“…Consistently, LIV-1 was expressed higher in carcinoma than in normal tissues and knockdown of LIV-1 by siRNA suppressed cell invasion in cervical carcinoma, suggesting the tumor promoting effect of this gene (12). In contrast, negative association of LIV-1 protein level with tumor size, grade and stage was reported in breast carcinoma tissues (18). In * P<0.05 (B) LIV-1 down-regulated cells (P11 and P18) showed ~40 to 60% reduction of proliferation after 48 h of culture with normal medium and 65 to 75% reduction after 72 h compared to P-EV cells.…”

Section: Discussionmentioning

confidence: 68%

LIV-1 enhances the aggressive phenotype through the induction of epithelial to mesenchymal transition in human pancreatic carcinoma cells

Unno

Satoh

Hirota³

et al. 2009

Int J Oncol

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Abstract. LIV-1 is a downstream target of STAT3 and is essential for the nuclear localization of Snail, a master regulator of epithelial to mesenchymal transition (EMT). Little is known about the association of LIV-1 with pancreatic carcinoma development, therefore, expression of LIV-1 mRNA was analyzed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in 9 cultured cell lines (8 carcinoma and 1 normal duct cell lines) and 24 pancreatic tissues (12 carcinoma and 12 normal tissues). Localization of this gene product was investigated by immunohistochemistry in 72 pancreatic carcinoma and the relation between its expression and clinicopathological findings was examined. To assess the function of LIV-1 in pancreatic carcinoma cells, stable siRNA expressing Panc-1 cells were generated. Higher expression of LIV-1 mRNA was found in both pancreatic carcinoma cell lines and pancreatic carcinoma tissues compared to normal duct cell line and histologically normal tissues, respectively. Immunohistochemical analysis revealed that LIV-1 expression was frequently found in 76.4% of pancreatic carcinoma tissues and its expression level was associated with tumor size and lymphatic infiltration. Down-regulated LIV-1 cells showed significant inhibition of anchorage-dependent or -independent proliferation and cell motility in vitro and reduction of tumor growth and metastasis in vivo. Furthermore, nuclear expression of Snail was decreased and E-cadherin expression was restored in LIV-1 siRNA expressing pancreatic carcinoma cells. These findings indicate that LIV-1 may be involved in acquisition of the aggressive phenotype of human pancreatic carcinoma cells through the induction of epithelial to mesenchymal transition. IntroductionLIV-1 is a member of new subfamily of zinc transporters, termed LZT (LIV-1 subfamily of ZIP zinc transporters) and is suggested to be located to the plasma membrane. It has been shown to act as a zinc transporter, leading to an increase in intracellular zinc levels (1). Zinc plays various roles in cell metabolism and is involved in cellular processes such as cell growth, differentiation and gene transcription (2,3), suggesting that its altered distribution might promote tumorigenesis. LIV-1 was originally identified as an estrogen-induced gene in the breast cancer cell line ZR-75-1 (4) and its expression was also shown to be correlated with lymph node involvement of the breast carcinoma, indicating a role for LIV-1 in metastasis (5).Epithelial to mesenchymal transition (EMT) is a general phenomenon that is an essential event in embryonic development, tissue remodelling and wound repair. During EMT, a loss of intracellular adhesion is observed along with extensive remodelling of the cytoskeleton and expression of components specific to a mesenchymal phenotype. Epithelial cells undergoing the transition to a mesenchymal phenotype also display an increased propensity for migration (6-8). Therefore, this transition is considered to be an important event during malignant tumor progression an...

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“…Zip6 is thought to be a prognostic indicator of estrogen receptorpositive (ER + ) breast cancer (Kasper et al , 2005 ). Interestingly, Zip6 protein levels are negatively associated with tumor grade, level, and size (Kasper et al , 2005 ). Consistent with this observation, Zip6 attenuation in ER + breast cancer cell …”

Section: Mammary Glandmentioning

confidence: 72%

“…(Shen et al , 2009 ;Lopez and Kelleher , 2010 ), increases mitochondrial membrane potential, and decreases apoptosis (Lopez and Kelleher , 2010 ). This functionally implicates Zip6 in mobilizing Zn 2 + from the endoplasmic reticulum (Taylor and Nicholson , 2003 ;Kasper et al , 2005 ) and modulating mechanisms that restrict epithelial-to-mesenchymal transition (EMT). Zip7 is localized to the endoplasmic reticulum where it functions to increase the mobilization of Zn 2 + into the cytoplasm (Hogstrand et al , 2009 ).…”

Section: Zip12mentioning

confidence: 99%

“…Several transporters are overexpressed (Zip6, Zip7, Zip10, and ZnT2) (Kagara et al , 2007 ;Taylor , 2008 ;Lopez et al , 2011 ), and the expression of ZnT1 is reduced (Lee et al , 2003 ); yet due to the marked heterogeneity of breast cancer subtypes, the functional consequences of these observations are only partially understood. Zip6 is thought to be a prognostic indicator of estrogen receptorpositive (ER + ) breast cancer (Kasper et al , 2005 ). Interestingly, Zip6 protein levels are negatively associated with tumor grade, level, and size (Kasper et al , 2005 ).…”

Section: Mammary Glandmentioning

confidence: 99%

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Zinc networks: the cell-specific compartmentalization of zinc for specialized functions

Hennigar

Kelleher²

2012

Biological Chemistry

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Zinc (Zn 2 + ) is the most abundant trace element in cells and is essential for a vast number of catalytic, structural, and regulatory processes. Mounting evidence indicates that like calcium (Ca 2 + ), intracellular Zn 2 + pools are redistributed for specifi c cellular functions. This occurs through the regulation of 24 Zn 2 + transporters whose localization and expression is tissue and cell specifi c. We propose that the complement and regulation of Zn 2 + transporters expressed within a given cell type refl ects the function of the cell itself and comprises a ' Zn 2 + network. ' Importantly, increasing information implicates perturbations in the Zn 2 + network with metabolic consequences and disease. Herein, we discuss our current understanding of Zn 2 + transporters from the perspective of a Zn 2 + network in four specifi c tissues with unique Zn 2 + requirements (mammary gland, prostate, pancreas, and brain). Delineating the entire Zn 2 + transporting network within the context of unique cellular Zn 2 + needs is important in identifying critical gaps in our knowledge and improving our understanding of the consequences of Zn 2 + dysregulation in human health and disease.

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Expression levels of the putative zinc transporter LIV‐1 are associated with a better outcome of breast cancer patients

Cited by 74 publications

References 43 publications

Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease

Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease

LIV-1 enhances the aggressive phenotype through the induction of epithelial to mesenchymal transition in human pancreatic carcinoma cells

Zinc networks: the cell-specific compartmentalization of zinc for specialized functions

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