ErbB2 Promotes Src Synthesis and Stability: Novel Mechanisms of Src Activation That Confer Breast Cancer Metastasis

Tan, Ming; Li, Ping; Klos, Kristine S.; Lü, Jing; Lan, Keng Hsueh; Nagata, Yoichi; Fang, Dexing; Tong, Jing; Yu, Dihua

doi:10.1158/0008-5472.can-04-2353

Cited by 93 publications

(89 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data proposing Src stabilization as new effector pathway of CUTL1, which mediates tumor invasion, are in accordance with a recent report demonstrating that Src protein upregulation and activation by ErbB2 is due to increased Src protein stability (Tan et al, 2005). Stabilizing Src protein levels might therefore represent a novel mechanism by which tumor-promoting signaling cascades exert their effect on tumor cell migration and invasion.…”

Section: Discussionsupporting

confidence: 92%

“…Stabilizing Src protein levels might therefore represent a novel mechanism by which tumor-promoting signaling cascades exert their effect on tumor cell migration and invasion. In contrast to ErbB2, which increased Src stability mainly through the inhibition of calpain protease activity (Tan et al, 2005), we show that in our cell systems the proteasome activity is essential for the CUTL1-dependent modulation of Src protein levels. In addition to decreased Src protein levels after CUTL1 knockdown, the activity of known Src-regulated downstream effectors such as small Rho GTPases (Rho, Rac and Cdc42) and ROCK is markedly impaired, culminating in reduced cell spreading and motility.…”

Section: Discussioncontrasting

confidence: 68%

See 1 more Smart Citation

CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

et al. 2007

View full text Add to dashboard Cite

Recently, we identified the homeodomain transcription factor CUTL1 as important mediator of cell migration and tumor invasion downstream of transforming growth factor b (TGFb). The molecular mechanisms and effectors mediating the pro-migratory and pro-invasive phenotype induced by CUTL1 have not been elucidated so far. Therefore, the aim of this study was to identify signaling pathways downstream of CUTL1 which are responsible for its effects on tumor cell migration. We found that the reduced motility seen after knock down of CUTL1 by RNA interference is accompanied by a delay in tumor cell spreading. This spreading defect is paralleled by a marked reduction of Src protein levels. We show that CUTL1 leads to Src protein stabilization and activation of Srcregulated downstream signaling molecules such as RhoA, Rac1, Cdc42 and ROCK. In addition, we demonstrate that CUTL1 decreases proteasome-mediated Src protein degradation, possibly via transcriptionally upregulating Cterminal Src kinase (Csk). Based on experiments using Src knockout cells (SYF), we present evidence that Src plays a crucial role in CUTL1-induced tumor cell migration. In conclusion, our findings linking the pro-invasive transcription factor CUTL1 and the Src pathway provide important new insights in the molecular effector pathways mediating CUTL-induced migration and invasion.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussioncontrasting

confidence: 68%

CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

et al. 2007

View full text Add to dashboard Cite

show abstract

“…We showed that the wild-type ErbB2-overexpressing 435.eB cells, ErbB2-activated V659E cells had increased tyrosine phosphorylation levels and kinase activities, and were more invasive in vitro and more metastatic in an animal model than the ErbB2 low-expressing parental MDA-MB-435 cells, control 435.neo cells and ErbB2 kinase-defective K753M cells (Tan et al, 2005).…”

Section: Upregulation and Activation Of Pkca By Erbb2mentioning

confidence: 86%

“…To elucidate the ErbB2 downstream signals that contribute to ErbB2-mediated breast cancer metastasis, we previously established in ErbB2-low-expressing MDA-MB-435 human breast cancer cells stable transfectants expressing either two ErbB2 mutants (V659E, a constitutive active form of ErbB2; K753M, a kinasedefective mutant), a wild-type ErbB2 or a control pcDNA3 vector ( Figure 1a and Nagata et al, 2004;Tan et al, 2005). We showed that the wild-type ErbB2-overexpressing 435.eB cells, ErbB2-activated V659E cells had increased tyrosine phosphorylation levels and kinase activities, and were more invasive in vitro and more metastatic in an animal model than the ErbB2 low-expressing parental MDA-MB-435 cells, control 435.neo cells and ErbB2 kinase-defective K753M cells (Tan et al, 2005).…”

Section: Upregulation and Activation Of Pkca By Erbb2mentioning

confidence: 99%

“…Activation of Src has been linked to the development of many human neoplasias, especially those of the colon, breast, lung and pancreas (Summy and Gallick, 2003). Src binds to ErbB2 and is activated in ErbB2-overexpressing cancer cells (Muthuswamy and Muller, 1995;Nagata et al, 2004;Tan et al, 2005). We recently showed that activation of ErbB2 can lead to increased Src protein synthesis and decreased Src protein degradation, resulting in Src protein upregulation and activation, which play critical roles in ErbB2-mediated breast cancer invasion and metastasis (Tan et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Sun

et al. 2006

Oncogene

View full text Add to dashboard Cite

Although ErbB2 is known to enhance breast cancer metastasis, the signaling events responsible for this remain elusive. a-Isozyme of protein kinase C (PKCa), which is involved in cancer development and progression, has been suggested to be activated by ErbB2 without direct evidence. In addition, the roles of PKCa in ErbB2-mediated cancer cell malignancy have not been clearly identified. In this study, we investigated whether ErbB2 can activate PKCa and determined what role PKCa plays in ErbB2-mediated breast cancer cell invasion. We expressed wild-type and mutant ErbB2 with altered signaling capacities in MDA-MB-435 breast cancer cells and revealed that overexpression or activation of ErbB2 in MDA-MB-435 cells upregulated and activated PKCa and that downregulation of ErbB2 by small-interfering RNA decreased the expression and activity of PKCa in BT474 breast cancer cells. These in vitro results were supported by data from breast cancer patient samples. In 150 breast cancer tumor samples, ErbB2-overexpressing tumors showed significantly higher positive rates of PKCa membrane immunohistochemistry staining than that of ErbB2-low-expressing tumors. Mechanistically, we found that PKCa is co-immunoprecipitated with Src and PKCa expression and activity can be decreased by Src inhibitor PP2 and by the expression of a dominantnegative mutant of Src. Moreover, ErbB2-mediated upregulation of urokinase-type plasminogen activator receptor (uPAR) is reduced by either the PKCa inhibitor Go6976 or the Src inhibitor PP2, and the combination of Go6976 with PP2 is superior to either agent alone in suppressing uPAR expression and cell invasion. These results demonstrate that PKCa is critical for ErbB2-mediated cancer cell invasion and provide valuable insights for current and future PKCa and Src inhibitor clinical trials.

show abstract

Biomarker‐driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer

et al. 2012

View full text Add to dashboard Cite

Src tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP-sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6-month survival. A Simon MinMax two-stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28-day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6-month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker-driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin-like growth factor-binding protein 2 [IGFBP2] “top scoring pairs” polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker-positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3′ untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6-month survival endpoint. As the frequency of biomarker-positive patients was very low (<3%), the study was closed. Although we were unable to conclude whether enriching for a subset of second/third line pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6-month survival, we demonstrate that testing pancreatic tumor samples for a biomarker-driven, multicenter study in metastatic pancreas cancer is feasible.

show abstract

ErbB2 Promotes Src Synthesis and Stability: Novel Mechanisms of Src Activation That Confer Breast Cancer Metastasis

Cited by 93 publications

References 49 publications

CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

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

Biomarker‐driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer

Contact Info

Product

Resources

About