Oestrogens, proteases and breast cancer. From cell lines to clinical applications

Human breast cancer is characterised by its high frequency of metastasis and its oestrogen responsiveness, allowing specific anti-oestrogen therapy. Oestrogens are promoting agents that stimulate early steps of mammary carcinogenesis. The availability of several oestrogen receptor (ER)-positive and ER-negative human breast cancer metastatic cell lines has allowed characterisation of several hormone-regulated genes, some of which are involved in growth and metastasis. Moreover, these models have allowed examination of the mechanisms by which hormone antagonists (anti-oestrogens and anti-progestins) act on their respective receptors to inhibit tumour growth. By contrast, no convenient in vitro models are available to investigate the mode of action of oestrogens and anti-oestrogens on non-malignant mammary cells. Among the oestrogen-regulated genes, some are also regulated by growth factors, such as the cathepsin D gene, whose overexpression in primary breast cancers has been associated with relapse and metastasis in several retrospective clinical studies. The mechanism and consequences of cathepsin D overexpression on metastasis are reviewed. From these studies on cell lines, new immunological and genetic probes have been raised that can be applied to breast cancer tissue to titrate in patients expression of different genes involved in the control of mammary tumour growth and invasion. These tissue markers should help to stratify primary breast cancers according to their ability to metastasise and respond to therapies and consequently to choose the best therapy. Over the next decade, these studies should lead to new therapeutical approaches of breast cancers which resist classical systemic therapies.