Oncogenes homologous to steroid receptors?
Oncogenes homologous to steroid receptors?
复制标题
致癌基因与类固醇受体同源？
作者：
M. Sluyser;J. Mester
SIR-Why do tumours that initially respond to hormone therapy lose their hormone responsiveness after a time and then grow autonomously? This problem is of great clinical importance, for instance in breast cancer where tumours that diminish in size after endocrine treatment almost invariably recur and then tend to progressively become nonresponsive. The discovery that many breast cancers consist of subclones of oestrogen receptor (ER)-positive and ER-negative cells1• 2 suggests that tumour progression is the survival of the'fittest'and most malignant ER-negative subtype. But where do the hormone-independent cells come from in the first place? Are they always present or are they derived from hormone-dependent cells? And how do these manage to survive and proliferate if they do not have the oestrogen receptor to give the proliferation signal?A general opinion is that the cells become hormone-independent because they have lost the receptor. But such cells should be unable to respond to their growth stimulus and so be eliminated from the tumour population. A more plausible alternative is that they have undergone a change that leads to their getting a growth signal even in the absence of ER. Steroid receptors interact with nuclear DNA at enhancer regions that regulate the transcriptional activity of structural genes3· 6• Perhaps a mutation in the enhancer leads to its activation of genes without the need for receptor to bind to it. However, it is unlikely that the loss of ER and a mutation in the enhancer region would occur simultaneously. We suggest another explanation, namely the appearance of aberrant receptor-like molecules that bind to DNA and give a proliferation signal even in the absence of oestrogen. Unlike traditional ligandbinding studies, the recently developed monoclonal antibodies to steroid receptors have made it possible to seek aberrant receptors which fail to bind steroids in hormone-independent cells. Thus immunoreactive glucocorticoid receptors have been detected in receptor deficient (r-), nuclear-transfer deficient (nt-) and nuclear-transfer increased (nti) mouse lymphoma variant cells 7, and this has been confirmed by the finding that mRNA encoded by the receptor gene in these variants is changed quantitatively and qualitatively8• In r-cells, one allele is altered so that no product is detectable with either steroid or antibody, while the other allele produces an immunoreactive polypeptide devoid of hormone-binding activity7• In nt-and nti lymphoma cell variants, the glucocorticoid receptors react abnormally with DNA9• 10. What are the structural changes associated with this abnormal functioning of receptors? In nti cells part of the recep-
