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

Abstract

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.

Kinase-Dependent and -Independent Roles for PTK6 in Colon Cancer

“…S1 A) and in most human colon tumors. In addition, manipulation of PTK6 expression did not have an impact on the activating tyrosine phosphorylation of two of its substrates, FAK (20) and BCAR1 (20) (data not shown), as previously demonstrated in human prostate cell lines (20), and in tumors that formed in mouse models of skin (16), and breast (29) cancer.…”

“…PTK6 has oncogenic substrates that are activated by tyrosine phosphorylation, including the transcription factor STAT3 (4, 27–29). We serum starved and stimulated SW620 cells stably expressing PTK6-WT, -YF and -KM to promote growth factor receptor-mediated PTK6 activation, and probed cell lysates for STAT3 activation (phosphorylation at tyrosine residue 705), as well as activation of the downstream effectors ERK1/2 (11) and ERK5 (20, 30).…”

“…Several studies indicate that PTK6 plays oncogenic roles in breast cancer [reviewed in (38)], and we recently demonstrated that Ptk6 contributes to tumor initiation and metastasis in an MMTV-ERBB2 mouse model of breast cancer (29). Although PTK6 contributes to epithelial cell differentiation in the normal intestine, it can also promote STAT3 activation and tumor initiation in the AOM/DSS mouse colon cancer model (4).…”

PTEN is a protein phosphatase that targets active PTK6 and inhibits PTK6 oncogenic signaling in prostate cancer

“…Mice with systemic disruption of Ptk6 exhibited enhanced growth and delayed differentiation in the small intestine, but they did not have a cancer phenotype 5 . Contrary to initial expectations, Ptk6 −/− mice were resistant to development of colon 6 , breast 7 , and skin 8 cancers in different mouse models, highlighting distinct oncogenic roles for the kinase and its context specific functions in vivo.…”

Genome-Wide Identification and Characterization of Tyrosine Kinases in the Silkworm, Bombyx mori

“…Tyrosine phosphorylation plays vital and ubiquitous roles in multi-cellular biology processes, including tissue differentiation, growth development, immune responses, cell adhesion, motility and apoptosis [ 9 , 14 , 15 , 16 , 17 , 18 , 19 ]. Therefore, mutation and malfunction of tyrosine kinase genes result in many diseases such as cancer and diabetes [ 20 , 21 , 22 , 23 ]. In history, TKs defined the prototypical class of oncogenes involved in numerous human malignancies [ 10 ].…”