The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells.

Syk is a protein tyrosine kinase that is widely expressed in haematopoietic cells. It is involved in coupling activated immunoreceptors to downstream signalling events that mediate diverse cellular responses including proliferation, differentiation and phagocytosis. Syk expression has been reported in cell lines of epithelial origin, but its function in these cells remains unknown. Here we show that Syk is commonly expressed in normal human breast tissue, benign breast lesions and low-tumorigenic breast cancer cell lines. Syk messenger RNA and protein, however, are low or undetectable in invasive breast carcinoma tissue and cell lines. Transfection of wild-type Syk into a Syk-negative breast cancer cell line markedly inhibited its tumour growth and metastasis formation in athymic mice. Conversely, overexpression of a kinase-deficient Syk in a Syk-positive breast cancer cell line significantly increased its tumour incidence and growth. Suppression of tumour growth by the reintroduction of Syk appeared to be the result of aberrant mitosis and cytokinesis. We propose that Syk is a potent modulator of epithelial cell growth and a potential tumour suppressor in human breast carcinomas.

Tumor growth of FGF or VEGF transfected MCF-7 breast carcinoma cells correlates with density of specific microvessels independent of the transfected angiogenic factor.

We have previously shown that fibroblast growth factor (FGF)-1-, FGF-4-, or vascular endothelial growth factor (VEGF/VPF)-transfected MCF-7 breast carcinoma cells growing as tumors in nude mice are tamoxifen resistant and/or estrogen independent. These transfectants provide opportunity for study of in situ tumor-induced angiogenesis promoted by the individual angiogenic factors under growth-promoting versus growth-inhibiting hormonal conditions. In the present study, vessels in tumors harvested at varying times after tumor cell injection were immunohistochemically highlighted and vessel morphology and topography were scored on a scale of 0 to 4 by blinded observers. In tumors produced by all cell lines under all growth-promoting hormonal conditions, there was significantly increased abundance (P < 0.05) of edge-associated and intratumor microvessels, but not of stromally located microvessels, when compared with tumor nodules harvested under growth-inhibiting conditions, regardless of the identity of the angiogenic factor or the hormonal treatment. Image analysis of bromodeoxyuridine (BrdU)-labeled nuclei of tumors produced by all cell lines under all hormonal conditions harvested at early time points showed that mean labeling indices were highest for hormonal conditions that produced the most robust growth in that particular cell line, implying that a high BrdU labeling index is a predictor of future tumor growth in individual tumors. These results confirm previous studies that established the importance of neovascularization for tumor growth and provide validation for use of these cell lines to study the process of angiogenesis in vivo. Study of gene expression in endothelial cells in edge-associated or intratumor vessels using this model might reveal mechanisms important in tumor-induced angiogenesis in human breast cancer.

Technetium-99m-sestamibi parathyroid scintigraphy: effect of P-glycoprotein, histology and tumor size on detectability.

UNLABELLED: The purpose of this study was to evaluate the effect of P-glycoprotein (P-gp) levels, predominant histology and tumor size on the detectability of parathyroid adenomas with 99mTc-sestamibi scans. Although previous studies have shown that positivity correlates with tumor size, false-negative studies have been reported with large tumors and true-positives reported with very small tumors. Recent investigations have reported rapid washout of sestamibi in malignant tumors because of high levels of P-gp, similar to that seen with multidrug chemotherapy resistance. Therefore, we postulated that this mechanism might account for false-negative studies in parathyroid tumors. Preliminary reports have suggested that the predominant histological subtype influences positivity on 99mTc-sestamibi parathyroid scans. METHODS: We studied 25 patients with surgically confirmed parathyroid adenomas with 99mTc-sestamibi parathyroid scans. The results of the imaging study were correlated with tissue P-gp levels, predominant histological subtype and size of the surgically removed glands. RESULTS: There were 21 true-positive and 4 false-negative results. The size of the adenomas ranged from 0.12 to 8.64 ml. We found no correlation between the results of the dual-phase 99mTc-sestamibi study and either the predominant cell type or the level of P-gp. Positivity did correlate with the size of the adenoma (p=0.73, p < 0.0001). We cannot exclude the possibility that P-gp and cell type may still play a role in individual cases, but we suspect that other yet to be determined factors may influence 99mTc-sestamibi detectability in addition to tumor size.