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CIP4 promotes metastasis in triple-negative breast cancer and is associated with poor patient prognosis.

Cerqueira OL, Truesdell P, Baldassarre T, Vilella-Arias SA, Watt K, Meens J, Chander H, Osório CA, Soares FA, Reis EM, Craig AW - Oncotarget (2015)

Bottom Line: This correlated with significant defects in 3D invasion of surrounding extracellular matrix by CIP4 KD TNBC cells when grown as spheroid colonies.In mammary orthotopic xenograft assays using both human TNBC cells (MDA-MB-231, HCC 1806) and rat MTLn3 cells, CIP4 silencing had no overt effect on tumor growth, but significantly reduced the incidence of lung metastases in each tumor model.In human invasive breast cancers, high CIP4 levels was significantly associated with high tumor stage, TNBC and HER2 subtypes, and risk of progression to metastatic disease.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.

ABSTRACT
Signaling via epidermal growth factor receptor (EGFR) and Src kinase pathways promote triple-negative breast cancer (TNBC) cell invasion and tumor metastasis. Here, we address the role of Cdc42-interacting protein-4 (CIP4) in TNBC metastasis in vivo, and profile CIP4 expression in human breast cancer patients. In human TNBC cells, CIP4 knock-down (KD) led to less sustained activation of Erk kinase and impaired cell motility compared to control cells. This correlated with significant defects in 3D invasion of surrounding extracellular matrix by CIP4 KD TNBC cells when grown as spheroid colonies. In mammary orthotopic xenograft assays using both human TNBC cells (MDA-MB-231, HCC 1806) and rat MTLn3 cells, CIP4 silencing had no overt effect on tumor growth, but significantly reduced the incidence of lung metastases in each tumor model. In human invasive breast cancers, high CIP4 levels was significantly associated with high tumor stage, TNBC and HER2 subtypes, and risk of progression to metastatic disease. Together, these results implicate CIP4 in promoting metastasis in TNBCs.

No MeSH data available.


Related in: MedlinePlus

CIP4 silencing alters EGFR signaling to Akt and ERK kinases(A) MDA-MB-231 Tripz or shCIP4 were treated with Dox (2 μg/ml for 48 hours) prior to serum starvation and treatment with EGF (50 ng/ml) for the indicated times (min.). Lysates were subjected to immunoblot with the indicated antibodies. Positions of molecular mass markers are indicated on the left. (B) Densitometry was performed and phosphoprotein levels were normalized to total protein levels, and expressed as fold change relative to time 0 (mean ± sem is shown for 4 separate blots from 2 experiments; *p < 0.05, **p < 0.01).
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Figure 2: CIP4 silencing alters EGFR signaling to Akt and ERK kinases(A) MDA-MB-231 Tripz or shCIP4 were treated with Dox (2 μg/ml for 48 hours) prior to serum starvation and treatment with EGF (50 ng/ml) for the indicated times (min.). Lysates were subjected to immunoblot with the indicated antibodies. Positions of molecular mass markers are indicated on the left. (B) Densitometry was performed and phosphoprotein levels were normalized to total protein levels, and expressed as fold change relative to time 0 (mean ± sem is shown for 4 separate blots from 2 experiments; *p < 0.05, **p < 0.01).

Mentions: To address whether CIP4 regulates EGFR signaling to downstream pathways, we profiled EGF-induced phosphorylation of the activation loop sites (T308) in Akt (pAkt) and Erk kinases (pErk) in Dox-treated vector and CIP4 KD cells. EGF treatment of CIP4 KD cells led to increased pAkt levels compared to control cells (Figure 2A/2B). This may be due to the increased EGFR levels in CIP4 KD cells. Despite elevated EGFR levels in CIP4 KD cells, EGF treatment led to less sustained activation of Erk kinase compared to control cells (Figure 2A/2B). Similar defects in EGFR signaling to Erk and Akt were observed in CIP4 KD lung adenocarcinoma cells [21], and these results implicate CIP4 in regulating EGFR levels and signaling.


CIP4 promotes metastasis in triple-negative breast cancer and is associated with poor patient prognosis.

Cerqueira OL, Truesdell P, Baldassarre T, Vilella-Arias SA, Watt K, Meens J, Chander H, Osório CA, Soares FA, Reis EM, Craig AW - Oncotarget (2015)

CIP4 silencing alters EGFR signaling to Akt and ERK kinases(A) MDA-MB-231 Tripz or shCIP4 were treated with Dox (2 μg/ml for 48 hours) prior to serum starvation and treatment with EGF (50 ng/ml) for the indicated times (min.). Lysates were subjected to immunoblot with the indicated antibodies. Positions of molecular mass markers are indicated on the left. (B) Densitometry was performed and phosphoprotein levels were normalized to total protein levels, and expressed as fold change relative to time 0 (mean ± sem is shown for 4 separate blots from 2 experiments; *p < 0.05, **p < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496225&req=5

Figure 2: CIP4 silencing alters EGFR signaling to Akt and ERK kinases(A) MDA-MB-231 Tripz or shCIP4 were treated with Dox (2 μg/ml for 48 hours) prior to serum starvation and treatment with EGF (50 ng/ml) for the indicated times (min.). Lysates were subjected to immunoblot with the indicated antibodies. Positions of molecular mass markers are indicated on the left. (B) Densitometry was performed and phosphoprotein levels were normalized to total protein levels, and expressed as fold change relative to time 0 (mean ± sem is shown for 4 separate blots from 2 experiments; *p < 0.05, **p < 0.01).
Mentions: To address whether CIP4 regulates EGFR signaling to downstream pathways, we profiled EGF-induced phosphorylation of the activation loop sites (T308) in Akt (pAkt) and Erk kinases (pErk) in Dox-treated vector and CIP4 KD cells. EGF treatment of CIP4 KD cells led to increased pAkt levels compared to control cells (Figure 2A/2B). This may be due to the increased EGFR levels in CIP4 KD cells. Despite elevated EGFR levels in CIP4 KD cells, EGF treatment led to less sustained activation of Erk kinase compared to control cells (Figure 2A/2B). Similar defects in EGFR signaling to Erk and Akt were observed in CIP4 KD lung adenocarcinoma cells [21], and these results implicate CIP4 in regulating EGFR levels and signaling.

Bottom Line: This correlated with significant defects in 3D invasion of surrounding extracellular matrix by CIP4 KD TNBC cells when grown as spheroid colonies.In mammary orthotopic xenograft assays using both human TNBC cells (MDA-MB-231, HCC 1806) and rat MTLn3 cells, CIP4 silencing had no overt effect on tumor growth, but significantly reduced the incidence of lung metastases in each tumor model.In human invasive breast cancers, high CIP4 levels was significantly associated with high tumor stage, TNBC and HER2 subtypes, and risk of progression to metastatic disease.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.

ABSTRACT
Signaling via epidermal growth factor receptor (EGFR) and Src kinase pathways promote triple-negative breast cancer (TNBC) cell invasion and tumor metastasis. Here, we address the role of Cdc42-interacting protein-4 (CIP4) in TNBC metastasis in vivo, and profile CIP4 expression in human breast cancer patients. In human TNBC cells, CIP4 knock-down (KD) led to less sustained activation of Erk kinase and impaired cell motility compared to control cells. This correlated with significant defects in 3D invasion of surrounding extracellular matrix by CIP4 KD TNBC cells when grown as spheroid colonies. In mammary orthotopic xenograft assays using both human TNBC cells (MDA-MB-231, HCC 1806) and rat MTLn3 cells, CIP4 silencing had no overt effect on tumor growth, but significantly reduced the incidence of lung metastases in each tumor model. In human invasive breast cancers, high CIP4 levels was significantly associated with high tumor stage, TNBC and HER2 subtypes, and risk of progression to metastatic disease. Together, these results implicate CIP4 in promoting metastasis in TNBCs.

No MeSH data available.


Related in: MedlinePlus