Where is the lesion in hormone-independent breast cancer?

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The estrogen receptor (ER) belongs to a superfamily of ligand-modulated transcription factors that, among other functions, play a role in both normal breast development and in the progression of breast cancer. The growth of many breast cancer cells appears to be dependent on the proliferative effects of estrogen, and this responsiveness correlates with the presence of a functional ER. The presence of ER on breast cancer cells is exploited beneficially when patients with ER-positive breast cancer are treated with antiestrogens that can block the growthpromoting effect of circulating estrogens. Unfortunately, however, 30% of patients with breast cancer present with ER-negative disease (/). These patients are traditionally considered insensitive to the proliferative and antiproliferative effects of estrogens and antiestrogens, respectively and, thus, are poor candidates for hormonal manipulation (2). In considering this clinical problem, two questions come to mind. First, will the simple introduction of functional ER into ER-negative tumor cells confer estrogen responsiveness? And second, if achieved, could this approach be a relevant treatment strategy for clinical intervention in hormone-independent breast cancer? Enormous effort has been put forth to determine whether or not stable expression of the ER is sufficient to confer estrogen responsiveness on cell lines that normally do not express the receptor. Six years ago, it was shown that ER-negative cells become estrogen responsive when co-transfected with ER and an exogenous estrogen-responsive reporter gene construct (3). However, hormone-dependent induction of exogenous gene constructs indicates only that some of the factors involved in the estrogen response may not be cell specific. It does not address whether the introduction of ER can stimulate endogenous estrogen-regulated genes. It now appears that the answer to this question is less straightforward and depends not only on the cell type into which the ER is introduced, but also on the levels of ER expression achieved, and, finally, on the particular estrogenregulated gene that is measured. Touitou et al. (4) have demonstrated that transfection of ER into ER-negative HeLa cells confers estrogen stimulation of endogenous cathepsin D gene expression, but not control of cell growth. The growth of these cells was unaffected by estrogen; however, this result could merely reflect the low level of ER expression (5-10 fmol/mg cytosolic protein) that was achieved. It was not until much higher levels of ER expression were obtained that the complexity of the estrogen response was fully appreciated. When physiological levels of ER are attained by stable transfection, it appears that, in certain cell types, including normal human mammary cells, the ER alone is not sufficient to evoke the estrogenic regulation of several important genes (pS2 and the progesterone receptor) (5,6). It is not surprising that other positive trans-acting factors may be required for the induction of specific genes or that repression of negative regulatory factors may be necessary for full estrogenic effects; this is a potentially fruitful area for future study. In light of these findings and those of several other studies (5,7,8), the study reported by Jiang and Jordan (9) in this issue of the Journal is of particular interest. Contrary to our established understanding of the proliferative effects of estrogen on ER-containing cells, an ER-dependent inhibition of cellular proliferation was observed in cells containing physiological or higher levels of introduced ER. These authors speculate that the reactivation or introduction of ER into ER-negative cells may be a new therapeutic approach to inhibit the growth of these tumors. But this is somewhat of a paradox: How can estrogen be