Epidermal growth factor receptors in intracranial and breast tumours: their clinical significance.

A method to determine the binding of epidermal growth factor (EGF) to the particulate fraction of the cell has been established and evaluated using rat liver, human placenta, and tumours of human breast and brain. Little EGF receptor (EGFR) activity was detected in normal or benign tumour tissues except for meningioma (positive in 95% samples), but EGFR were present in 43% of 131 breast tumours and 75% of 55 primary cerebral tumours. Despite the strong inverse correlation between EGFR activity and oestrogen receptors in breast tumours and a tendency for high levels of EGFR activity to be associated with glioblastoma multiforme, analysis showed that EGFR was of little prognostic significance in patients with tumours of either breast or brain.

Levels of androgen conjugates and oestrone sulphate in patients with breast cysts.

Plasma and cyst fluid were obtained from patients with palpable breast cysts and analysed for androgen conjugates and oestrone sulphate content by radioimmunoassay. Concentrations of androgen conjugates in cyst fluids varied from 15.6 to 475.5 mumols/l. These levels were much greater than those in plasma (1.3-5.2 mumols/l) and there was no association between values in cyst aspirates and plasmas obtained from the same individuals. Levels of oestrone sulphate in breast cyst fluids (1.5-744.0 nmol/l) were also generally in excess of those in plasma (2.0-59.9 nmol/l) and again no relationship was evident between concentrations in cyst fluid and the circulation. Neither was there a relationship between levels of androgen conjugate and oestrone sulphate in plasma. In contrast, a highly significant correlation (P less than 0.001) was identified between the androgen conjugate and oestrone sulphate content of cyst fluids. Levels of both androgen conjugates and oestrone sulphate were also significantly different in groups of cysts subdivided according to electrolyte classification, cysts with low Na+:K+ ratios having higher steroid concentrations than those with high Na+:K+ ratios. The biological significance of the relationship between the two conjugates in cyst fluids remains unclear but it is suggested that the accumulation of these steroids involves a common mechanism.

Oestrogen receptors, lactate dehydrogenase and cellularity in human breast cancer.

Oestrogen receptor (ER) concentrations in breast tissues are almost universally expressed in relation to total soluble protein, though the latter does not fully correct for gross variations in receptor concentration due to variations in tissue cellularity. It was considered possible that the concentration of a specific glycolytic enzyme might be a better index and reflection of tumour cellularity. Measurements of the concentrations of lactate dehydrogenase (LDH), oestrogen receptor and total soluble protein and estimates of tumour cellularity were therefore performed on 98 breast tissues (80 breast cancers, 18 benign tissues). Cellularity and the concentrations of oestrogen receptor, lactate dehydrogenase and total soluble protein were significantly higher in breast cancers than in the benign tissues. The concentration of oestrogen receptors (positives only) was, as expected, related to tissue cellularity (correlation coefficient, r = 0.35). The concentrations of both LDH and total soluble protein were also both strongly related to tissue cellularity (correlation coefficients r = 0.67 and 0.75, respectively), and to each other (r = 0.78). These results suggest that (1) total soluble protein concentration is a good index of cellularity and (2) there is unlikely to be any additional value in expressing receptor concentrations relative to LDH since the latter appears to be a 'typical' soluble protein.

Epidermal growth factor binding in intracranial neoplasms: preliminary biochemical and clinicopathological findings.

The binding capacity for epidermal growth factor (EGF) was determined in 34 intracranial neoplasms (14 glioblastoma, seven low-grade gliomas, six meningiomas, and seven others) and four specimens of normal brain by using [I125]EGF. EGF binding and binding affinity of the sites in the tumour and brain samples were compared to placenta and rat liver. All specimens of normal brain were negative. Ten of 14 glioblastoma specimens contained EGF binding (level range 10-39,660 fmol/mg protein), however, ligand binding affinity was high in only three tumours. Only one of nine low-grade gliomas contained EGF binding activity. Five of six meningiomas contained EGF binding sites (level range 49-776 fmol/mg protein) and binding affinity was high in two. When present EGF binding activity was found in all cellular fractions except the cytosol. There were no clinical or histopathological features within major tumour groups that were predictive of either high or specific EGF binding activity. These preliminary studies have confirmed that EGF receptor-like activity is present in the particulate fractions of intracranial neoplasms of both mesenchymal and neuroctodermal origin. In a large proportion of these tumours the EGF binding affinity is low, suggesting either a less specific or truncated EGF binding site.

Oestrone sulphate, adipose tissue, and breast cancer.

Oestrone sulphate, the oestrogen in highest concentration in the plasma, may play a role in the induction and growth of breast cancers. By enzymolysis and radioimmunoassay, oestrone sulphate concentrations were measured in 3 biological fluids. High concentrations of the conjugate (up to 775 nmol/l) were detected in breast cyst fluids from some premenopausal women, the concentrations in blood plasma (0.91-4.45 nmol/l) being much lower. Concentrations in the plasmas from postmenopausal women with (0.23-4.63 nmol/l) or without (0.18-1.27 nmol/l) breast cancer were still lower. Oestrone sulphate concentration in cow's milk or cream (0.49-0.67 nmol/l) was also low: dietary intake in these fluids is probably of little consequence. The capacity of breast tissues for hydrolysis of oestrone sulphate was examined in two ways: In tissue slices incubated with 85 pM (3H) oestrone sulphate solution at 37 degrees C, cancers (131-412 fmol/g tissue/hr) and adipose tissues (23-132 fmol/g tissue/hr) hydrolysed significantly more sulphate than did benign tissues (1-36 fmol/g tissue/hr). In tissue homogenates incubated with 5-25 microM [3H] oestrone sulphate at 37 degrees much higher capacities for hydrolysis (nmol/g tissue/hr) were demonstrated with a Km of 2-16.5 microM: cancers (34-394) and benign tissues (9-485) had significantly higher sulphatase activities than adipose tissues (9-39). On a protein basis, however, the sulphatase activities in the 3 tissues were comparable. It is concluded that oestrone sulphate is present in breast cysts and blood plasma and that in vitro, the conjugated hormone can be hydrolysed by breast tissues. The biological significance of these findings in vivo remains to be established.

Metabolism of oestradiol by human mammary tumour 800 x g supernatants pretreated with dihydrolipoic acid.

Incubation of human mammary tumour 800 x g supernatants with [3H]oestradiol after preincubation for 10 min at 0 degrees C with 10 mM dihydrolipoic acid resulted in metabolism of oestradiol. This was noted in 12 malignant tumours, 8 of which contained measurable oestrogen receptor levels. In 2 benign tumours lacking measurable levels of receptor, dihydrolipoic acid pretreatment had no effect. This metabolism was further stimulated by pretreatment with NAD, NADP and the anti-oestrogen Tamoxifen (ICI 46,474). When incubations were carried out in an O2 atmosphere using oxygenated buffers, the effect was suppressed.

Oestradiol-17 beta and prolactin levels in rat peripheral plasma.

Radioimmunoassay methods for the determination of oestradiol-17 beta and prolactin have been examined for their reliability and applied to the measurement of hormone concentrations in the plasmas from male and female rats. Prolactin was detectable in all samples (greater than 7 ng RP-1 ng/ml) but the concentration of oestradiol-17 beta was below the sensitivity of the method (greater than 0-10 ng/100 ml) in ovariectomized females. Plasma oestradiol-17 beta concentration rose gradually from metoestrus to proestrus and fell to barely detectable levels in oestrus. Plasma prolactin concentration was very variable even for rats in the same stage of the oestrous cycle but values were minimal in the afternoon of diestrus and a surge in secretion occurred in the afternoon of proestrus. In addition to the stage of the oestrous cycle, the prolactin concentration was influenced by mode of blood collection, degree of haemolysis and choice of serum or plasma. There was no correlation between the concentration of prolactin and that of oestradiol-17 beta in the same sample of plasma.