Novel Glucocorticoid Stimulated Breast Cancer c-fms RNA Binding Nuclear Protein

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• 作者：Chambers ; Setsuko K. ; Folk ; Nancy L.
• 刊名：Journal of the Society for Gynecologic Investigation
• 出版年：1998
• 出版时间：January 2, 1998
• 年：1998
• 卷：5
• 期：1, Supplement 1
• 页码：74A
• 全文大小：173 K

文摘

Our laboratory has been studying the role of the c-fms proto-oncogene in the neoplastic progression of breast and other epithelial cancers. C-fms, which encodes for the tyrosine kinase receptor for the macrophage colony stimulating factor, CSF-1, is expressed by the majority of breast cancers, but not by normal breast tissue. When c-fms is transfected into normal mammary epithelial cells, it leads to enhanced invasiveness and metastasis. Elevated levels of c-fms/CSF-1 are associated with poor prognosis in the invasive cancers. Glucocorticoids (GC), which induce differentiation of normal mammary tissues, markedly upregulate c-fms RNA and protein expression in breast cancer cells. Such increased levels by GCs result in an enhanced invasiveness of breast cancer cells in vitro. Our current work shows that the mechanism underlying the 28 fold elevation in c-fms levels by GCs is largely post-transcriptional. Protein synthesis inhibition has a minimal effect in resting breast cancer cells, but leads to an attenuation of GC stimulation of c-fms RNA, as well as to a marked increase in c-fms mRNA decay in GC stimulated cells, as measured by actinomycin-D chase experiments. This suggests that a GC stimulated regulatory protein may have a c-fms RNA stabilizing function in breast cancer cells. We have discovered, by RNA gel shift and UV crosslinking assays, that GCs stimulate the binding of a novel 66 kDa breast cancer nuclear protein, to a 69 nt sequence in the 3′ untranslated region of the c-fms transcript. This c-fms RNA binding protein is increased 50 fold by GCs; the binding is specific for the sense sequences, and is completely inhibited by RU486. PCR mediated deletion of these 69 nt sequences abolishes c-fms RNA binding under both resting and GC stimulated conditions. No other GC stimulated cytoplasmic or nuclear protein was found which bound to the almost 4000 nt of 5′ c-fms RNA sequences. The 69 nt c-fms sequence is not AU-rich, and has no homology with other elements known to confer instability, nor to any other known sequence. We hypothesize that the 66 kDa GC stimulated nuclear breast cancer protein, by binding to a 69 nt c-fms RNA fragment, results in stabilization of the c-fms transcript, thus leading to overexpression of the c-fms proto-oncogene in breast cancers.