Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors

Tan, Ming; Li, P.; Sun, Mianen; Yin, Guosheng; Yu, Dihua

doi:10.1038/sj.onc.1209361

Cited by 92 publications

(79 citation statements)

References 35 publications

(54 reference statements)

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“…We and others (Guy et al, 1992;Tan et al, 1997Tan et al, , 2005Tan et al, , 2006aTan et al, , 2006b) have previously shown that the overexpression of ErbB2 increases the transformation and/ or metastatic potentials of breast cancer cells. In addition, ErbB2 has been shown to activate signaling molecules that regulate bioenergetic metabolism, such as Ras, PI3K/Akt, mTOR and Src (Yarden and Sliwkowski, 2001;Zhou et al, 2004;Tan et al, 2005Tan et al, , 2006bZhang et al, 2007). A recent study investigated the role of lactate dehydrogenase A (LDH-A), a critical enzyme in the glycolysis pathway, in the tumor maintenance of neu-transformed mouse mammary epithelial cells, showing that compared to normal cells, cancer cells have deregulated bioenergetic metabolism and increased glycolysis (Fantin et al, 2006).…”

Section: Introductionmentioning

confidence: 69%

Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

et al. 2009

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ErbB2 has been shown to activate signaling molecules that may regulate glucose metabolism. However, there is no evidence reported to directly link ErbB2 to glycolysis, and the mechanism underlying ErbB2-enhanced glycolysis is poorly understood. In this study, we investigated the role and mechanism of ErbB2 in regulating glycolysis. We found that ErbB2-overexpressing cells possessed a significantly higher level of glycolysis when compared to the ErbB2-low-expressing cells, and the downregulation of ErbB2 markedly decreased glycolysis. Overexpression of ErbB2 increased the expression of glycolysis-regulating molecules lactate dehydrogenase A (LDH-A) and heat shock factor 1 (HSF1). ErbB2 activated HSF1, indicated by the increased HSF1 trimer formation, and promoted HSF1 protein synthesis. HSF1 bound to LDH-A promoter and the downregulation of HSF1 reduced the expression of LDH-A and subsequently decreased cancer cell glycolysis and growth. Moreover, the glycolysis inhibitors, 2-deoxyglucose and oxamate, selectively inhibited the growth of ErbB2-overexpressing cells. Taken together, this study shows that in human breast cancer cells, ErbB2 promotes glycolysis at least partially through the HSF1-mediated upregulation of LDH-A. This pathway may have a major role in regulating glucose metabolism in breast cancer cells. These novel findings have important implications for the design of new approaches to target ErbB2-overexpressing breast cancers.

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Section: Introductionmentioning

confidence: 69%

Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

et al. 2009

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“…PKCα levels may especially be increased in breast cancer patients with low or negative estrogen receptor levels (Lahn et al, 2004). Activation of PKCα by ErbB2 through Src has been shown to promote breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors (Tan et al, 2006). There is evidence that loss of PKC function contributes to the anti-proliferative action of a number of anticancer compounds (Musashi et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Delphinidin inhibits cell proliferation and invasion via modulation of Met receptor phosphorylation

Syed

Afaq

Sarfaraz

et al. 2008

Toxicology and Applied Pharmacology

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The HGF/Met signaling pathway is deregulated in majority of cancers and is associated with poor prognosis in breast cancer. Delphinidin, present in pigmented fruits and vegetables possesses potent anti-oxidant, anti-inflammatory and anti-angiogenic properties. Here, we assessed the antiproliferative and anti-invasive effects of delphinidin on HGF-mediated responses in the immortalized MCF-10A breast cell line. Treatment of cells with delphinidin prior to exposure to exogenous HGF resulted in the inhibition of HGF-mediated (i) tyrosyl-phosphorylation and increased expression of Met receptor, (ii) phosphorylation of downstream regulators such as FAK and Src and (iii) induction of adaptor proteins including paxillin, Gab-1 and GRB-2. In addition, delphinidin treatment resulted in significant inhibition of HGF-activated (i) Ras-ERK MAPKs and (ii) PI3K/AKT/mTOR/p70S6K pathways. Delphinidin was found to repress HGF-activated NFκB transcription with a decrease in (i) phosphorylation of IKKα/β and IκBα, and (ii) activation and nuclear translocation of NFκB/p65. Inhibition of HGF-mediated membrane translocation of PKCα as well as decreased phosphorylation of STAT3 was further observed in delphinidin treated cells. Finally, decreased cell viability of Met receptor expressing breast cancer cells treated with delphinidin argues for a potential role of the agent in the prevention of HGF-mediated activation of various signaling pathways implicated in breast cancer.

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“…A prior report (32) using breast cancer cell lines showed that overexpression of HER-2 led to up-regulation and activation of phosphokinase C (PKC). In breast cancer patients' samples, HER-2 overexpressing tumors showed significantly higher PKC membrane staining compared with HER-2 low expressing tumors.…”

Section: Discussionmentioning

confidence: 99%

uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues

Meng¹,

Tripathy²,

Shete

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

145

104

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Overexpression of urokinase plasminogen activator system or HER-2 (erbB-2) in breast cancer is associated with a poor prognosis. HER-2 overexpression is caused by HER-2 gene amplification. The anti-HER-2 antibody trastuzumab significantly improves clinical outcome for HER2-positive breast cancer. Drugs that target the uPA system are in early clinical trials. The aims of this study were to determine whether urokinase plasminogen activator receptor (uPAR) gene amplification occurs and whether analysis of individual tumor cells (TCs) in the blood or tissue can add information to conventional pathological analysis that could help in diagnosis and treatment. Analysis of individual TCs indicates that uPAR amplification occurs in a significant portion of primary breast cancers and also circulating tumor cells (CTCs) from patients with advanced disease. There was complete concordance between touch preps (TPs) and conventional pathological examination of HER-2 and uPAR gene status in primary tumors. There was also excellent concordance of HER-2 gene status between primary tumors and CTCs provided that acquisition of HER-2 gene amplification in CTCs was taken into account. Unexpectedly, gene amplification of HER-2 and uPAR occurred most frequently in the same TC and patient, suggesting a biological bias and potential advantage for coamplification. Expression of HER-2 and uPAR in primary tumors predicted gene status in 100 and 92% of patients, respectively.

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Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors

Cited by 92 publications

References 35 publications

Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

Delphinidin inhibits cell proliferation and invasion via modulation of Met receptor phosphorylation

uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues

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