Search

The elucidation of the molecular mechanisms responsible for the hormonal control of cell proliferation in breast cancer has been the object of intense research. Because most breast cancers are initially dependent upon estrogens for continued growth, much of this research has focused on the role of estrogen receptor (ER) in the control of gene expression and mitosis (1), and on its use as a marker for hormone responsiveness and prognosis (2). In addition, progesterone receptor (PR), as both a mediator of hormonal responses and as a product of estrogen action on breast cancer cells, has been studied extensively as a tumor marker (3) and in terms of its regulation by estrogen agonists and antagonists (4). Although its function in breast cancer is unknown, the presence as well as the induction of PR has been coupled to estrogen-induced proliferative responses in breast cancer cells. An improved understanding of the function and regulation of expression of these transcription factors is emerging from studies of the structure, composition and dynamics of the receptor proteins and the genes that encode them. The cloning and molecular analysis of all of the known steroid receptors has led to the definition of common functional domains and a proposed mechanism by which they interact with responsive genes, via cis-acting DNA enhancer elements, in normal and neoplastic tissues (5, 6) (7). For ER and PR, these studies have been aided by the availability of a number of monoclonal antibody probes directed against specific regions of each receptor (8, 9). In addition, the same antibodies have been used to develop validated quantitative and histochemical immunoassays for ER and PR in a variety of hormone-responsive tissues and related cancers. Such assays have proved particularly useful in the evaluation of ER and PR in breast tumor extracts (10), in frozen and paraffin-embedded tissues and tumor sections (11, 12, 13) (14) (15) and in needle biopsies (16) (17). This paper summarizes the results of recent studies on ER and PR structure, composition and activity in breast cancer cells as a function of agonist and antagonist binding.

Present research in the field of clinical breast cancer is focussed on new diagnostic methods and on the development of new treatment modalities. A number of modern cell biological parameters such as oncogenes, growth factors and secretory proteins, appear to be important prognostic factors because they strongly influence the behaviour of a tumor with respect to metastatic pattern, extent of cellular differentiation, growth rate and the development of therapy resistance. These factors are also relevant for the development of new treatment strategies. In this paper we will deal first with these new diagnostic methods and then we will summarize new developments in the treatment of breast cancer.

The elucidation of the molecular mechanisms responsible for the hormonal control of cell proliferation in breast cancer has been the object of intense research. Because most breast cancers are initially dependent upon estrogens for continued growth, much of this research has focused on the role of estrogen receptor (ER) in the control of gene expression and mitosis [1], and on its use as a marker for hormone responsiveness and prognosis [2]. In addition, progesterone receptor (PR), as both a mediator of hormonal responses and as a product of estrogen action on breast cancer cells, has been studied extensively as a tumor marker [3] and in terms of its regulation by estrogen agonists and antagonists [4]. Although its function in breast cancer is unknown, the presence as well as the induction of PR has been coupled to estrogen-induced proliferative responses in breast cancer cells. An improved understanding of the function and regulation of expression of these transcription factors is emerging from studies of the structure, composition, and dynamic of the receptor proteins and the genes that encode them. The cloning and molecular analysis of all of the known steroid receptors has led to the definition of common functional domains and a proposed mechanism by which they interact with responsive genes, via cis-acting DNA enhancer elements, in normal and neoplastic tissues [5, 6, 7]. For ER and PR, these studies have been aided by the availability of a number of monoclonal antibody probes directed against specific regions of each receptor [8, 9]. In addition, the same antibodies have been used to develop validated quantitative and histochemical immunoassays for ER and PR in a variety of hormone-responsive tissues and related cancers. Such assays have proved particularly useful in the evaluation of ER and PR in breast tumor extracts [10], in frozen and paraffin-embedded tissues and tumor sections [11, 12, 13, 14, 15], and in needle biopsies [16, 17]. This paper summarizes the results of recent studies on ER and PR structure, composition, and activity in breast cancer cells as a function of agonist and antagonist binding.

The workshop entitled “Markers for Differentiation and Malignancy” comprised sixteen short papers that on hindsight could be divided into three groups: Cell nuclear parameters and breast cancer prognosis; use of breast differentiation and other antigens identified by monoclonal antibodies in histopathoiogy; and the use of anti-breast monoclonal antibodies for sero-diagnostic and therapeutic purposes.

There are few studies reporting the combined use of hormones and non-hormonal agents. In addition, in vitro methods are now available to predict the effectiveness of oestrogens, fluorouracil, methotrexate and adriamycin. We wished to undertake a trial of methotrexate, adriamycin, fluorouracil, and oestrogen in patients with breast cancer following determination of their cellular predictive indices. However, it was first necessary to determine the tolerability of the drug regimen. This paper reports the results of our preliminary phase I trial.

The advent of monoclonal antibodies has opened a new area of breast cancer therapy, and because of unique aspects compared to conventional therapy new approaches have to be defined, and new problems addressed. Monoclonal antibodies have to be selected specifically for therapy, ideal characteristics have to be defined, conjugates must be selected, conjugation methods must be evaluated, and appropriate target antigens have to be identified. One aspect of the latter that must be taken into consideration is the complexity and cell heterogeneity in expression of most antigens that have an appropriate tissue or tumor cell specificity for therapy. This paper will address the question of antigenic heterogeneity in approaching the use of monoclonal antibodies for therapy of breast cancer.

Although there has been a great deal of study of the epidemiology of breast cancer, it is only fairly recently that people have begun to think seriously about the possibilities for prevention.(1,2) Although there are some clues, it is not yet possible to provide an unequivocal answer to the question. Rather, this paper is intended to be a contribution to a debate with particular consideration of two potential approaches to primary prevention of breast cancer: hormonal manipulation and dietary change.

Although single cell heterogeneity in breast and other tumors has become a well-established observation, neither the underlying reasons for it nor its biological significance are yet clearly understood. However, it exemplifies the dynamic nature of a tumor cell population; it may play an important role in the effectiveness of breast cancer therapy, especially with the new possibilities for monoclonal antibody (MoAb) therapy; and it also could be used in improving diagnosis and prognostic evaluation. The type of single cell heterogeneity addressed in this paper is quantitative heterogeneity, especially that which has been revealed with monoclonal antibodies to surface antigens, but it must be emphasized that quantitative single cell heterogeneity has also been observed for other cell components, such as enzymes (1), secretory products (2), and hormone receptors (3).

The word ‘cure’was used in the title of Hal stead’s paper in 1894 in which he described his technique of radical mastectomy (1) and this had so powerful an effect that the treatment remained standard for the next 50 years. There appeared to be little practical point in investigating factors which might be related to prognosis since patients received identical treatment whether their outlook was good or bad. Clinical or pathological staging was used mainly to compare results between centres but was not used to determine treatment. Histological grading was used as an academic excercise.

The effect of steroid hormones is mediated by the interaction with specific hormone receptors of the target cell. It was obvious, that this concept should be applied to the management of so-called hormone responsive tumours. Steroid-hormone receptors - mostly oestrogen receptors - have been detected in the following neoplasias of the female reproductive system: cervical cancer, endometrial cancer, ovarian cancer, breast cancer. Our information on the implication and function of receptor protein in these tumours is still incomplete and their presence does not necessarily indicate responsiveness to endocrine manipulation. Although there is a reasonable chance of successful hormonal treatment of carcinomas of the endometrium and the breast, the same does not hold true for cervical and ovarian cancers. The present paper deals with the practical value of receptor measurements in patients with endometrial, ovarian or breast cancer.