RESUMO
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.
Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Mamárias Experimentais/genética , Proteínas Tirosina Quinases/genética , Receptor ErbB-2/genética , Infecções por Retroviridae/genética , Infecções Tumorais por Vírus/genética , Animais , Carcinogênese , Proliferação de Células , Proteína Substrato Associada a Crk/genética , Proteína Substrato Associada a Crk/metabolismo , Cruzamentos Genéticos , Progressão da Doença , Feminino , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Animais/virologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Vírus do Tumor Mamário do Camundongo/patogenicidade , Vírus do Tumor Mamário do Camundongo/fisiologia , Camundongos , Camundongos Knockout , Fosforilação , Proteínas Tirosina Quinases/deficiência , Receptor ErbB-2/metabolismo , Infecções por Retroviridae/metabolismo , Infecções por Retroviridae/patologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Infecções Tumorais por Vírus/metabolismo , Infecções Tumorais por Vírus/patologiaRESUMO
Protein tyrosine kinase 6 (PTK6, also called BRK) is an intracellular tyrosine kinase expressed in the majority of human breast tumors and breast cancer cell lines, but its expression has not been reported in normal mammary gland. To study functions of PTK6 in vivo, we generated and characterized several transgenic mouse lines with expression of human PTK6 under control of the mouse mammary tumor virus (MMTV) long terminal repeat. Ectopic active PTK6 was detected in luminal epithelial cells of mature transgenic mammary glands. Lines expressing the MMTV-PTK6 transgene exhibited more than a two-fold increase in mammary gland tumor formation compared with nontransgenic control animals. PTK6 activates signal transducer and activator of transcription 3 (STAT3), and active STAT3 was detected in PTK6-positive mammary gland epithelial cells. Endogenous mouse PTK6 was not detected in the normal mouse mammary gland, but it was induced in mouse mammary gland tumors of different origin, including spontaneous tumors that developed in control mice, and tumors that formed in PTK6, H-Ras, ERBB2 and PyMT transgenic models. MMTV-PTK6 and MMTV-ERBB2 transgenic mice were crossed to explore crosstalk between PTK6 and ERBB2 signaling in vivo. We found no significant increase in tumor incidence, size or metastasis in ERBB2/PTK6 double transgenic mice. Although we detected increased proliferation in ERBB2/PTK6 double transgenic tumors, an increase in apoptosis was also observed. MMTV-PTK6 clearly promotes mammary gland tumorigenesis in vivo, but its impact may be underrepresented in our transgenic models because of induction of endogenous PTK6 expression.
RESUMO
PURPOSE: To evaluate the patency and healing characteristics of a woven polyester fabric-covered stent in the canine model. METHODS: Twenty-four self-expanding covered stents were placed in the infrarenal aorta and bilateral common iliac arteries of eight dogs and evaluated at 1 (n = 2), 3 (n = 2), and 6 (n = 4) months. Stent assessment was done using angiography prior to euthanasia, and light and scanning electron microscopy. RESULTS: Angiographically, just prior to euthanasia, 8 of 8 aortic and 14 of 16 iliac endovascular covered stents were patent. Histologically, the stented regions showed complete endothelialization 6 months after graft implantation. A neointima had formed inside the stented vessel regions resulting in complete encasement of the fabric-covered stent by 3 months after graft implantation. Medial compression with smooth muscle cell atrophy was present in all stented regions. Explanted stent wires, examined by scanning electron microscopy, showed pitting but no cracks or breakage. CONCLUSION: The covered stent demonstrated predictable healing and is effective in preventing stenosis in vessels 10.0 mm or greater in diameter but does not completely preclude stenosis in vessels 6.0 mm or less in diameter.
