ErbB3-Dependent Motility and Intravasation in Breast Cancer Metastasis

Xue, Chengsen; Liang, Fengyi; Mahmood, Radma; Vuolo, Magalis; Wyckoff, Jeffrey; Qian, Hong; Tsai, Kun Lin; Kim, Mimi; Locker, Joseph; Zhang, Zhong Yin; Segall, Jeffrey E.

doi:10.1158/0008-5472.can-05-0550

Cited by 84 publications

(76 citation statements)

References 42 publications

(38 reference statements)

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“…Phosphorylation of HER2, HER3 and AKT was elevated upon suppression of BTG2. Although HER2 can homo-or heterodimerize with EGFR or HER3, HER2/ HER3 heterodimers are the most potent mitogenic and transforming complex (Hynes et al, 2001), and heterodimers containing HER3 have been implicated in enhanced cell migration and invasiveness (Sithanandam et al, 2005;Xue et al, 2006). Activation of HER pathway in shBTG2 cells was coincident with the increase in NRG1b, a ligand that binds to both HER3 and HER4 receptors (Zhang et al, 1997) and epiregulin, a component of the 18-gene breast-to-lung metastatic gene expression signature (Minn et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

et al. 2011

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The B-cell translocation gene-2 (BTG2), a p53-inducible gene, is suppressed in mammary epithelial cells during gestation and lactation. In human breast cancer, decreased BTG2 expression correlates with high tumor grade and size, p53 status, blood and lymph vessel invasion, local and metastatic recurrence and decrease in overall survival, suggesting that suppression of BTG2 has a critical role in disease progression. To analyze the role of BTG2 in breast cancer progression, BTG2 expression was knocked down in mammary epithelial cells. Suppression of BTG2 enhances the motility of cells in vitro and tumor growth and metastasis in vivo. The effects of BTG2 knockdown are mediated through stabilization of the human epidermal growth factor receptor (HER) ligands neuregulin and epiregulin and activation of the HER2 and HER3 receptors, leading to elevated AKT phosphorylation. Suppression of HER activation using the tyrosine kinase inhibitor lapatinib abrogates the effects of BTG2 knockdown, including the increased cell migration observed in vitro and the enhancement of tumorigenesis and metastasis in vivo. These results link BTG2-dependent effects on tumor progression to ErbB receptor signaling, and raise the possibility that targeted inhibition of this pathway may be relevant in the treatment of breast cancers that have reduced BTG2 expression.

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Section: Discussionmentioning

confidence: 99%

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

et al. 2011

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“…NRG is mitogenic for most mammary carcinoma cell lines, 82,[222][223][224][225] and can also stimulate motility and invasiveness of these cells. 209,[225][226][227] In ERBB2-over-expressing breast tumor cells, G1 progression after NRG stimulation was associated with ERBB2 transactivation of ERBB3 and stimulation of the PI3K pathway. 228 Contributions of ERBB3 and/or the ERBB2/ ERBB3 complex to these phenotypic effects of NRG has been confirmed by use of anti-ERBB2 or anti-ERBB3 antibodies 211,212,229 or of a dominant-negative ERBB3 construct.…”

Section: Erbb3 In Normal and Neoplastic Tissues Cell Transformation Bmentioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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“…The most probably rationale is that elisidepsin treatment could affect cells on the lipidic bilayer membrane, preferentially containing high levels of ErbB3 receptor, and this could enhance the activity of the different tested drugs (CDDP, TAX or gemcitabine). In this regard, tumors that harbor overexpression of ErbB3 could be good candidates to perform this type of combinational studies, such as metastatic breast or lung tumors (33,34). …”

Section: Discussionmentioning

confidence: 99%

ErbB3 expression predicts sensitivity to elisidepsin treatment: inï¿½vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines

et al. 2012

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Abstract.Irvalec ® (elisidepsin trifluoroacetate, PM02734) is a novel marine-derived cyclic peptide belonging to the Kahaladide family of compounds, currently in clinical trials with preliminary evidence of antitumor activity. Previous studies have shown a correlation between elisidepsin sensitivity and expression of the ErbB3 receptor in a panel of NSCLC cell lines. We have studied the effect of elisidepsin on the ErbB3 pathway, characterizing the expression of all members of the ErbB (HER) family of receptors and their main downstream signaling effectors, such as Akt and MAPK. Interestingly, we observed a downregulation of ErbB3 upon elisidepsin treatment that correlates with a reduction in the Akt phosphorylation levels in the most sensitive cell lines, whereas ErbB3 levels are not affected in the less sensitive ones. Also, we observed that the basal levels of ErbB3 protein expression show a significant correlation with cell viability response against elisidepsin treatment in 14 different cell lines. Furthermore, we analyzed the combination of elisidepsin with different chemotherapeutics agents, such as cisplatin, paclitaxel and gemcitabine, in a panel of different breast (MDA-MB-435, MDA-MB-231 and MCF7), lung (HOP62, DV90 and A549) and colorectal cancer cell lines (DLD1 and HT29). IC 50 values for the different drugs were tested. We observed a synergistic effect in all cell lines tested with any chemotherapeutic agent. More importantly, the two in vitro elisidepsin-resistant cell lines (MDA-MB-231 and HOP62) presented a synergistic effect in combination with cisplatin and paclitaxel, respectively. These results provide a rationale for further development of these combinations in an ongoing clinical trial.

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ErbB3-Dependent Motility and Intravasation in Breast Cancer Metastasis

Cited by 84 publications

References 42 publications

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

The ERBB3 receptor in cancer and cancer gene therapy

ErbB3 expression predicts sensitivity to elisidepsin treatment: inï¿½vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines

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