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Characterization of Protein Tyrosine Kinases from Human Breast Cancer: Involvement of the c-src Oncogene Product¹

Department of Hematology, Laboratory of Medical Enzymology [A. E. O-K., G. R., E. A. C. M. v. B., A. A. M., G. E. J. S.], and Department of Surgery [A. H.], University Hospital Utrecht, 3508 GA Utrecht, The Netherlands

Tyrosine phosphorylation is an important regulatory mechanism in response to the action of growth factors and oncogenes. Since many oncogenes code for tyrosine kinases, increased or altered oncogene expression may be reflected in increased tyrosine kinase activity. In a recent study (Hennipman et al., Cancer Res., 49: 516–521, 1989), we found that the tyrosine kinase activity of the cytosolic and membrane fractions of malignant human breast tissue was significantly higher compared to the benign or the normal breast tissue. Moreover, the increase in the cytosolic fractions was found to be of prognostic value. In the present study we determined the protein tyrosine kinase (PTK) activity of another 72 breast cancer specimens, and it could be shown again that the PTK activity in all 72 of these tumors was elevated compared to normal controls. We characterized these cytosolic PTKs by anion exchange chromatography using fast protein liquid chromatography, and it could be shown that at least two different forms of PTK exist. Using antibodies against a number of known oncogene products, we could determine that at least 70% of the PTK activity in the cytosol originated from the presence of the c-src oncogene product. Both of the PTK activity peaks seen in the fast protein liquid chromatography patterns could be precipitated with the anti-Src antibody. Furthermore, using the MCF-7 breast cancer cell line, it could be shown that the antibody against c-src also precipitated a part of the cytosolic PTK activity. In normal human peripheral lymphocytes, no precipitation of the cytosolic and membrane PTK activity could be achieved using the anti-Src antibody. Inasmuch as the cytosolic PTK activity parallels the malignancy in breast tumors (Hennipman et al., Cancer Res., 49: 516–521, 1989), and the majority of this activity is precipitated by anti-Src antibodies, the c-src protooncogene may play a key role in the manifestation of breast cancer.

¹ Supported by the Netherlands Cancer Foundation (UUKC Grant 89-01).

² To whom requests for reprints should be addressed, at Department of Hematology, Laboratory of Medical Enzymology, University Hospital Utrecht, P. O. Box 85500, 3508 GA Utrecht, The Netherlands

Received 3/16/92. Accepted 6/23/92.

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