HIF-1α-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion

Pires, Isabel; Blokland, Nina; Broos, Agnieke Wt; Poujade, Flore-Anne; Senra, Joana; Eccles, Suzanne A.; Span, Paul N.; Harvey, Amanda; Hammond, Ester M.

doi:10.4161/cbt.29822

Cited by 21 publications

(21 citation statements)

References 41 publications

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“…A recent study found that ERBB2 can promote PTK6 protein stability through negative regulation of calpain, a calcium-dependent, non-lysosomal cysteine protease, in breast cancer cell lines. 25 PTK6 expression is also regulated at the transcriptional 26 and post transcriptional 27 levels by HIF-1 α . HIF-1 expression is positively regulated by ERBB2, 28 and it is required for ERBB2-mediated mammary gland tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Protein tyrosine kinase 6 promotes ERBB2-induced mammary gland tumorigenesis in the mouse

2015

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Protein tyrosine kinase 6 (PTK6) expression, activation, and amplification of the PTK6 gene have been reported in ERBB2/HER2-positive mammary gland cancers. To explore contributions of PTK6 to mammary gland tumorigenesis promoted by activated ERBB2, we crossed Ptk6−/− mice with the mouse mammary tumor virus-ERBB2 transgenic mouse line expressing activated ERBB2 and characterized tumor development and progression. ERBB2-induced tumorigenesis was significantly delayed and diminished in mice lacking PTK6. PTK6 expression was induced in the mammary glands of ERBB2 transgenic mice before tumor development and correlated with activation of signal transducer and activator of transcription 3 (STAT3) and increased proliferation. Disruption of PTK6 impaired STAT3 activation and proliferation. Phosphorylation of the PTK6 substrates focal adhesion kinase (FAK) and breast cancer anti-estrogen resistance 1 (BCAR1; p130CAS) was decreased in Ptk6−/− mammary gland tumors. Reduced numbers of metastases were detected in the lungs of Ptk6−/− mice expressing activated ERBB2, compared with wild-type ERBB2 transgenic mice. PTK6 activation was detected at the edges of ERBB2-positive tumors. These data support roles for PTK6 in both ERBB2-induced mammary gland tumor initiation and metastasis, and identify STAT3, FAK, and BCAR1 as physiologically relevant PTK6 substrates in breast cancer. Including PTK6 inhibitors as part of a treatment regimen could have distinct benefits in ERBB2/HER2-positive breast cancers.

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Section: Discussionmentioning

confidence: 99%

Protein tyrosine kinase 6 promotes ERBB2-induced mammary gland tumorigenesis in the mouse

2015

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“…Although among breast cancer subtypes, TNBCs express the lowest level of PTK6 transcript (22), PTK6 protein is expressed in patients with TNBCs and TNBC cell lines (20,23). Both PTK6 transcript and protein levels have prognostic significance within this subtype, with higher levels associated with worse prognosis (20,23,24). Furthermore, PTK6 protein expression in TNBC cells can also be induced by known oncogenic stimuli; for example, hypoxiainducible factor 1a/2a activity promotes PTK6 expression (20).…”

Section: Introductionmentioning

confidence: 99%

PTK6 Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation

et al. 2016

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Patients with triple-negative breast cancers (TNBC) are at high risk for recurrent or metastatic disease despite standard treatment, underscoring the need for novel therapeutic targets and strategies. Here we report that protein tyrosine kinase 6 (PTK6) is expressed in approximately 70% of TNBCs where it acts to promote survival and metastatic lung colonization. PTK6 downregulation in mesenchymal TNBC cells suppressed migration and three-dimensional culture growth, and enhanced anoikis, resistance to which is considered a prerequisite for metastasis. PTK6 downregulation restored E-cadherin levels via proteasome-dependent degradation of the E-cadherin repressor SNAIL. Beyond being functionally required in TNBC cells, kinase-active PTK6 also suppressed E-cadherin expression, promoted cell migration, and increased levels of mesenchymal markers in nontransformed MCF10A breast epithelial cells, consistent with a role in promoting an epithelial-mesenchymal transition (EMT). SNAIL downregulation and E-cadherin upregulation mediated by PTK6 inhibition induced anoikis, leading to impaired metastatic lung colonization in vivo. Finally, effects of PTK6 downregulation were phenocopied by treatment with a recently developed PTK6 kinase inhibitor, further implicating kinase activity in regulation of EMT and metastases. Our findings illustrate the clinical potential for PTK6 inhibition to improve treatment of patients with high-risk TNBC.Cancer Res; 76(15); 4406-17. Ó2016 AACR.

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“…PTK6 expression is also induced in prostate tumors and cell lines (Zheng et al, 2012); relocalization of PTK6 from the nucleus to cytoplasm was reported in prostate cancer cells (Derry et al, 2003). In breast cancer cells, PTK6 expression has been shown to be mediated by hypoxia via multiple mechanisms; PTK6 protein is stabilized by HSP90 (Kang et al, 2012) and is transcriptionally upregulated by HIF-1α and HIF-2α (Regan Anderson et al, 2013), additionally PTK6 protein can be upregulated in a post-translational manner in response to hypoxia (Pires et al, 2014). PTK6 has been identified as a transcriptional target of CREB, and its expression is upregulated by p90RSK2 phosphorylation of CREB (Jin et al, 2013).…”

Section: Expressionmentioning

confidence: 99%

“…PTK6 binds with IGF-1R to mediate IGF-1 signaling promoting anchorage-independent growth (Irie et al, 2010). PTK6 expression is upregulated by hypoxia and promotes hypoxia-mediated breast cancer progression (Aubele et al, 2009;Kang et al, 2012;Pires et al, 2014).…”

Section: Breast Cancermentioning

confidence: 99%

PTK6 (protein tyrosine kinase 6)

Mathur¹,

Tyner²

2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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HIF-1α-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion

Cited by 21 publications

References 41 publications

Protein tyrosine kinase 6 promotes ERBB2-induced mammary gland tumorigenesis in the mouse

Protein tyrosine kinase 6 promotes ERBB2-induced mammary gland tumorigenesis in the mouse

PTK6 Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation

PTK6 (protein tyrosine kinase 6)

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