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Until recently, there has been little knowledge on the growth control of oestrogen receptor (ER)-negative ductal carcinoma in situ (DCIS) and invasive breast cancer. The recent development of DCIS models, such as transgenic mice, cell-line xenograft models and, importantly, in vivo human DCIS xenograft models has facilitated the investigation and understanding of the control of growth of early pre-invasive breast lesions. Recent studies have shown that ER-negative DCIS, unlike ER-positive DCIS, is hormone independent and does not respond to anti-oestrogen treatment. Moreover, DCIS of the comedo type utilises type I tyrosine kinase growth factors, such as epidermal growth factor receptor (EGFR) and c-erbB-2, in receptor signalling for growth. New data underscore the importance of EGFR as the major modulating growth factor receptor in the control of proliferation in the breast. Pre-clinical studies performed on human DCIS xenografts in nude mice suggest a potential role for EGFR tyrosine kinase inhibitors (EGFR-TKIs). More specifically, ZD1839, a novel orally active and selective EGFR-TKI, has been shown to produce a response in DCIS through a decrease in epithelial proliferation. These findings have enhanced our knowledge of signal transduction pathways in cancer and indicate that tyrosine kinase blockade of EGFR has potential for the treatment and chemoprevention of DCIS. It is hoped that further advances in this area and evaluation of EGFR-TKIs in Phase II/III clinical trials will allow their therapeutic potential as anticancer agents to be appreciated.
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Hormonal therapy leads to improved survival in oestrogen receptor (ER) positive early breast cancer and long-term responses in advanced disease. However, resistance to such therapy is a serious clinical problem. This article considers the data for and against there being a significant role for the oncogene HER-2 in such resistance. Transfection of HER-2 into MCF-7 cells leads to resistance to tamoxifen but data differ in relation to the oestrogen dependence of such cells. A number of retrospective studies have been conducted of HER-2 status in adjuvant trials of tamoxifen. Most of these also suggest a negative role but individually the studies do not have the statistical power to be conclusive. Recent studies in the neoadjuvant context have shown a significant antiproliferative effect of endocrine therapy in HER-2 positive/ER positive tumours but this is much less than in HER-2 negative/ER positive tumours. It is concluded that incomplete hormonal resistance results from co-expression of HER-2 and ER and that this may differ between different hormonal agents.
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Hormones are important regulators of growth. By stimulating proliferation, hormones may increase the risk of mutation and at the same time stimulate the replication of the mutated cell. Thus, hormones are complete carcinogens. A direct carcinogenic effect of oestrogen in man is known from the occurrence of vaginal carcinomas in girls born of mothers who were treated with oestrogen during pregnancy. There are also experimental animal studies indicating that even peptide hormones may induce malignant tumours.
An excellent example is the so-called enterochromaffin-like cell (ECL-cell) carcinoid of the stomach, which is caused by hypergastrinaemia and where the pathogenesis is diffuse hyperplasia, linear and nodular hyperplasia, dysplasia (with micronodules), intramucosal carcinoid, and invasive carcinoid. This sequence of events can be followed not only histopathologically but also by means of image DNA cytometry of the nuclei of the ECL-cells. As soon asclear-cut neoplasia is present, the cytometric DNA distribution pattern switches from the normal diploid type to an aneuploid one. The hyperplastic lesions are all reversible, as soon as the hypergastrinaemia is eliminated.
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Introduction
Endocrine therapy has now been used as an effective treatment for breast cancer for 100 years. It was the first successful systemic treatment for cancer, initially becoming accepted following George Beatson's (1896) observations that, in a proportion of pre-menopausal women with advanced breast cancer, bilateral oophorectomy resulted in disease regression. Over the subsequent 75 years, several other endocrine therapies for breast cancer were developed, including other surgical approaches to hormone ablation therapy such as adrenalectomy (Huggins & Dao 1953) and hypophysectomy (Luft & Olivecrona 1953), and hormonal additive therapies, such as the use of pharmacological doses of androgens, oestrogens, progestogens and glucocorticoids. However, as none of these approaches led to a significant improvement in the rates of tumour regression, clinicians' enthusiasm in the 1960s and early 1970s became focused on the use of newly developing cytotoxic chemotherapy regimens. Then, in the 1970s, tamoxifen, and subsequently a range of other new endocrine agents, became available which were of low toxicity and generally well tolerated - high-dose oestrogens were quickly replaced by tamoxifen, and adrenalectomy by aromatase inhibitors. Measurement of hormone receptor levels also became available, allowing better selection of patients whose tumours might be hormonally responsive. In addition, some of the limitations of cytotoxic drugs in breast cancer were starting to become apparent.
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the use of aromatase inhibitors (AIs) for early breast cancer in postmenopausal women has prompted interest in these drugs being used for chemoprevention. Chemoprevention of breast cancer –selective oestrogen receptor modulators (SERMs
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The interaction between cell death and cell proliferation determines the growth dynamics of all tissues. Studies are described here which relate the changes in proliferation and apoptosis that occur in human breast cancer during medical therapeutic manoeuvres. Xenograft studies strongly support the involvement of increased apoptosis as well as decreased proliferation after oestrogen withdrawal, and limited studies in clinical samples confirm the involvement of both processes. Cytotoxic chemotherapy induces increases in apoptosis within 24 h of starting treatment. However, after 3 months therapy the residual cell population shows apoptotic and proliferation indices much below pretreatment levels. Further molecular studies of this "dormant" population are important to characterise the mechanism of their resistance to drug therapy. The early changes in proliferation and apoptosis may provide useful intermediate response indices.
