Impact of protein tyrosine kinase 6 (PTK6) on human epidermal growth factor receptor (HER) signalling in breast cancer

Ludyga, Natalie; Anastasov, Nataša; Gonzalez-Vasconcellos, Iria; Ram, Manuela; Höfler, Heinz; Aubele, Michaela

doi:10.1039/c0mb00286k

Cited by 29 publications

(32 citation statements)

References 39 publications

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“…As recently shown by us, specific and efficient siRNAs for PTK6 knockdown were identified as described (19). The siRNAs for HER2 knockdown led to a specific and effective downregulation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The infections were conducted in triplicates. The infection efficiency of T47D and JIMT-1 cells was measured by fluorescence-activated cell sorting as described previously (19).…”

Section: Lentiviral Transductions Of Breast Cancer Cellsmentioning

confidence: 99%

“…For SDS-PAGE and the subsequent Western blot analysis, T47D and JIMT-1 breast cancer cells were treated as described previously (19 , and tubulin as a loading control (T5168, Sigma). The following peroxidase-conjugated secondary antibodies were used: anti-rabbit (NA934V) and anti-mouse (NA931V; GE Healthcare).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…PTK6 was also shown to regulate the cell cycle (18). PTK6 knockdown led to a diminished phosphorylation of STAT3, (p38) MAPK, and PTEN, as well as to a reduced migration of breast cancer cells (15,19).…”

Section: Introductionmentioning

confidence: 99%

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Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells

Ludyga

Anastasov

Rosemann

et al. 2013

Molecular Cancer Research

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Breast cancer is the most common malignancy in women of the Western world. One prominent feature of breast cancer is the co-and overexpression of HER2 and protein tyrosine kinase 6 (PTK6). According to the current clinical cancer therapy guidelines, HER2-overexpressing tumors are routinely treated with trastuzumab, a humanized monoclonal antibody targeting HER2. Approximately, 30% of HER2-overexpressing breast tumors at least initially respond to the anti-HER2 therapy, but a subgroup of these tumors develops resistance shortly after the administration of trastuzumab. A PTK6-targeted therapy does not yet exist. Here, we show for the first time that the simultaneous knockdown in vitro, compared with the single knockdown of HER2 and PTK6, in particular in the trastuzumab-resistant JIMT-1 cells, leads to a significantly decreased phosphorylation of crucial signaling proteins: mitogen-activated protein kinase 1/3 (MAPK 1/3, ERK 1/2) and p38 MAPK, and (phosphatase and tensin homologue deleted on chromosome ten) PTEN that are involved in tumorigenesis. In addition, dual knockdown strongly reduced the migration and invasion of the JIMT-1 cells. Moreover, the downregulation of HER2 and PTK6 led to an induction of p27, and the dual knockdown significantly diminished cell proliferation in JIMT-1 and T47D cells. In vivo experiments showed significantly reduced levels of tumor growth following HER2 or PTK6 knockdown. Our results indicate a novel strategy also for the treatment of trastuzumab resistance in tumors. Thus, the inhibition of these two signaling proteins may lead to a more effective control of breast cancer.

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Section: Resultsmentioning

confidence: 99%

“…The infections were conducted in triplicates. The infection efficiency of T47D and JIMT-1 cells was measured by fluorescence-activated cell sorting as described previously (19).…”

Section: Lentiviral Transductions Of Breast Cancer Cellsmentioning

confidence: 99%

Section: Western Blot Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells

Ludyga

Anastasov

Rosemann

et al. 2013

Molecular Cancer Research

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“…BRK has been implicated in regulating EGF signaling. It sensitizes mammary epithelial cells to EGF (42) and enhances EGF receptor (EGFR) signaling (43,44), and its suppression impairs the signaling response to EGF (45). BRK mediates these effects, at least in part, by inhibiting receptor downregulation, both through phosphorylation of EGFR, which disrupts ubiquitination of the receptor by CBL (46), and by phosphorylation of the BRK-binding protein ARAP1 (47).…”

Section: Discussionmentioning

confidence: 99%

Protein-tyrosine Phosphatase 1B Antagonized Signaling by Insulin-like Growth Factor-1 Receptor and Kinase BRK/PTK6 in Ovarian Cancer Cells*

Fan

Lin

Lucito³

et al. 2013

Journal of Biological Chemistry

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Background: Multiple signaling pathways are disrupted in ovarian cancer, but the role of protein phosphatases is not appreciated. Results: PTP1B antagonizes signaling by IGF-1R and BRK/PTK6 in ovarian cancer cells. Conclusion: Decreased expression of PTP1B in ovarian cancer cells promotes migration, invasion, proliferation, and survival. Significance: PTP1B, which dephosphorylates the insulin receptor and is an important therapeutic target in diabetes, may antagonize IGF-1-induced signaling in specific contexts.

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Three‐dimensional microtissues essentially contribute to preclinical validations of therapeutic targets in breast cancer

et al. 2016

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A 3D microtissues using T47D and JIMT‐1 cells were generated to analyze tissue‐like response of breast cancer cells after combined human epidermal growth factor receptor 2 (HER2)‐targeted treatment and radiation. Following lentiviral knockdown of HER2, we compared growth rate alterations using 2D monolayers, 3D microtissues, and mouse xenografts. Additionally, to model combined therapeutic strategies, we treated HER2‐depleted T47D cells and 3D microtissues using trastuzumab (anti‐HER2 antibody) in combination with irradiation. Comparison of HER2 knockdown with corresponding controls revealed growth impairment due to HER2 knockdown in T47D 2D monolayers, 3D microtissues, and xenografts (after 2, 12, and ≥40 days, respectively). In contrast, HER2 knockdown was less effective in inhibiting growth of trastuzumab‐resistant JIMT‐1 cells in vitro and in vivo. Combined administration of trastuzumab and radiation treatment was also analyzed using T47D 3D microtissues. Administration of both, radiation (5 Gy) and trastuzumab, significantly enhanced the growth inhibiting effect in 3D microtissues. To improve the predictive power of potential drugs—as single agents or in combination—here, we show that regarding tumor growth analyses, 3D microtissues are highly comparable to outcomes derived from xenografts. Considering increased limitations for animal experiments on the one hand and strong need of novel drugs on the other hand, it is indispensable to include highly reproducible 3D microtissue platform in preclinical analyses to validate more accurately the capacity of future drug‐combined radiotherapy.

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Impact of protein tyrosine kinase 6 (PTK6) on human epidermal growth factor receptor (HER) signalling in breast cancer

Cited by 29 publications

References 39 publications

Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells

Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells

Protein-tyrosine Phosphatase 1B Antagonized Signaling by Insulin-like Growth Factor-1 Receptor and Kinase BRK/PTK6 in Ovarian Cancer Cells*

Three‐dimensional microtissues essentially contribute to preclinical validations of therapeutic targets in breast cancer

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