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Epidemiologists have established that women with small families, and particularly nulliparae, are prone to develop breast cancer later in life. We report that physiological mammary hypervascularity may be an intermediate reason against the background that breast-core vascularity is normal in pregnancy but pathological in the vascularisation of cancer. We examined breast 'core' vascularity in nulliparae during their potential reproductive life and in parous women after their last birth but before their menopause. Fifty clinically normal pre-menopausal non-pregnant women (100 breasts) were studied daily for one 'luteal positive' menstrual cycle. Their parity history varied from zero to five babies. Under controlled domestic conditions each wore a special electronic thermometric bra to automatically record breast 'core' temperature changes as a measure of mammary tissue blood flow. In the nulliparae there was a rise of breast vascularity throughout reproductive life. In the parous women, a year or so after each birth, breast vascularity was reset at a lower level than before the pregnancy; thereafter, as in nulliparae, there was progressive increase in mammary vascularity until the menopause.

Radiation used in breast-conserving therapy (BCT) for early breast cancer, to eradicate residual malignant cells after tumour resection, induces DNA damage and cell death. Little is known about the effect of the commonly used doses of radiation therapy on normal breast tissue. Under physiological conditions, p53 plays a role in maintaining genomic stability and regulating progression through the cell cycle. In normal glandular breast tissue, p53 expression is very low, as is proliferative activity. The purpose of this study was to investigate the levels of p53 expression and proliferative activity in non-malignant glandular epithelium of the breast after BCT. The immunohistochemical expression of p53 and Ki-67 was semiquantitatively correlated in non-malignant glandular epithelium in biopsies before and after BCT in 24 women with breast cancer. In 18 cases, a recurrence was diagnosed and in the remaining cases, the clinical suspicion was not histologically confirmed. In addition, in six cases with contralateral breast cancer, the same immunohistochemical evaluation was performed in tissue from both breasts. The mean interval between the two surgical interventions was 50 months. The percentage of p53 immunoreactive epithelial cells in normal breast tissue was significantly (P < 0.01) higher after radiation therapy than before in the ipsilateral side (0.2 per cent +/- 0.3 and 4.6 per cent +/- 4.5, respectively). Ki-67 immunoreactivity was also significantly increased (P < 0.001) after radiation therapy, from 0.6 per cent to an average of 4.8 per cent in epithelial cells. In contrast, in the patients with contralateral breast cancer, the levels of p53 and Ki-67 immunoreactivity in the normal glandular breast tissue were comparable to the ipsilateral side (P = 0.7 and P = 0.1, respectively). In conclusion, increased expression of p53 and Ki-67 is present in normal glandular breast tissue, even 2-5 years after radiation therapy.

Gap junctional intercellular communication (GJIC) has been proposed as a cellular mechanism for tumour suppression and there is experimental evidence in support of this. If aberrant GJIC contributes to the formation of human breast tumours, one might expect that the connexins (gap junction proteins) expressed by epithelial cells in normal human breast would be down-regulated in tumour epithelial cells, or that tumour cells might show aberrant expression of other connexin family members. This study examines the immunocytochemical expression of connexins 26 (Cx26) and 43 (Cx43) in normal human breast, 11 benign breast lesions, two special-type carcinomas, and 27 invasive carcinomas of no special histological type (NST). Cx26 generally was not expressed at detectable level in normal human breast, but punctate Cx43 immunostaining of the myoepithelial cells was found. Cx43 staining of the myoepithelium was also a feature of the benign lesions and ductal carcinoma in situ (DCIS). In general, the epithelial cells of benign lesions failed to stain for either connexin. Similarly, a lobular carcinoma did not express Cx26 or Cx43, but there was punctate Cx43 in the epithelial cells of a mucoid carcinoma. Cx26 was up-regulated in the carcinoma cells of 15 of the 27 invasive NST carcinomas, although the staining was usually cytoplasmic and heterogeneous. Cx43 was expressed by stromal cells, possibly myofibroblasts, in all NST carcinomas. Furthermore, there was heterogeneous Cx43 expression in the carcinoma cells of 14 of the 27 NST carcinomas and the staining was often intercellular and punctate, characteristic of functional connexins. Up-regulated of Cx26 and/or Cx43 in the carcinoma cells of over two-thirds of invasive lesions of NST is not necessarily inconsistent with a tumour suppressor role for GJIC. However, the role of gap junctions in the formation and progression of solid human tumours is likely to be more complex than indicated from experimental systems.

Response to cytotoxic agents is assumed to be related to the concentration of drug achieved within tumour tissue. It is also often assumed that, given similar tissue concentrations of drug, normal tissues are less responsive to the same cytotoxic agents. This can partly be explained by the number of cells in normal tissues that are differentiated. These non dividing cells, in a stable testing phase of the cell cycle (G0) are less susceptible to cytotoxic damage. Little is actually known about the relationship between tumour drug concentrations and those in the tissue of the tumour-bearing organ. In this study, we compared doxorubicin concentrations in paired samples of tumour and normal breast tissue from 17 previously untreated women undergoing mastectomy. The relative cellularities of both specimens were estimated by measuring their DNA content. There was wide variation in intra-tumoural doxorubicin concentrations (range, 220-1,590 ng/g). Normal tissue also showed marked inter-patient variation (range, 81-1,000 ng/g). For a single patient the tumour drug concentrations were significantly higher than those in normal breast tissue (P less than 0.05), and tumour: normal tissue ratios ranged from 1.27 to 8.30. Where doxorubicin concentration was expressed in terms of the relative cellularity of the tissues, there was no significant difference between, drug concentrations in the tumour and those in normal breast tissue (tumour: normal ratios, 1.1:1.8). There was a significant correlation (r = 0.76, P less than 0.05) between peak serum values and tumour concentrations of drug. No correlation was found between drug concentrations achieved and the histological grade or oestrogen receptor status of the breast cancer.