Abstract
Abstract Local-regional radiotherapy is one of the major therapeutic means in the management of breast cancer. However, besides the therapeutic effect, studies have shown that irradiation promotes malignant behavior of cancer cells both in vitro and in vivo by activating several tumor invasion and metastatic molecules. In this regard, ascertaining the molecular alterations contributing to this radiation-induced response is imperative. Accordingly, we investigated the role of radiation-induced NO-dependent nitrosylation in the transcription of invasion and metastatic genes in human breast adenocarcinoma cells. Human MCF-7 cells either mock irradiated, exposed to 2Gy (IR), treated with L-NAME (NOS inhibition) or BAY-11-7082 (phosphorylation inhibition) and then exposed to 2Gy, were examined for modulations in the transcriptional response of 93 tumor invasion and metastasis signaling genes. Cells treated with β-estradiol and mock-irradiated MDA-MB-231 cells were used as positive controls. Compared to mock irradiated cells, real time QPCR profiling revealed that 20 of 29 IR-induced genes including Birc3, Casp8, Ctgf, Ctsk, Htatip2, Kras, Map2k7, Mgat5, Mta2, Nme1, Nme2, Nme4, Pax5, Pten, Runx1, Serpinb5, Syk, Timp1, Timp2 and Timp4 were completely suppressed with NOS inhibition. Conversely, as opposed to NOS inhibition, IR-induced phosphorylation inhibition either failed to suppress or further induced the expression of these IR-induced genes. Furthermore, β-estradiol treatment revealed upregulation of 16 of these 20 IR-induced nitrosylation-dependent molecules and serves as a positive control for the study. More importantly, the highly metastatic, MDA-MB-231 cell line showed a robust induction in the expression of 15 of these 20 IR-induced nitrosylation-dependent genes. Taken together, these data imply that IR induces the expression of tumor invasion and metastatic genes and more importantly, may regulate the radiation-activated invasion and metastatic phenotype in breast adenocarcinoma cells. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-07-02.
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