Novel Roles of Arnt in Breast Tumor Progression, Metastasis and Therapy

ARNT has long been deemed as a general partner to HIF-1 in hypoxia in mediating tumor growth. Unlike HIF-1 which would be degraded in normoxic condition, ARNT expresses ubiquitously and constitutively in cells. In response to xenobiotics, the heterodimers of ARNT/AhR could recognize the xenobiotic response element (XRE) of target gene thus promote gene transcription, most notably the CYP1A1, which is important in detoxification. In addition, SIM-1 (single-minded 1), SIM-2, and ARNT were reported to involve in the normal neural development of embryos. Despite the functions that have been mentioned above, ARNT has been revealed recently in the regulation of CD30-mediated NF-B activity. To extend and clarify the pathophysiological role of ARNT well, we devote to study the requirement of ARNT in EGF-regulated tumorigenesis. Our previous report showed that ARNT could associate with c-Jun in response to EGF and bind to the CRE site of the COX-2 promoter, resulting in the transcriptional activation of the COX-2 gene as well as squamous cell carcinoma formation and metastasis in normoxia. In addition, we found that Sp1/ARNT/c-Jun complex is responsible for EGF-induced gene expression, including 12-lipoxygenase and p21 WAF1/CIP1. Since eicosanoids such as PGE2 and 12-HETE produced by COX-2 and 12-lipoxygenase, respectively have been indicated in metastatic progression, we are curious about whether EGF-activated ARNT signaling participates in cancer cell metastasis. More recently, we identified that ARNT also mediated the EGF-induced cytokines expression in tumor cells. We raise the hypothesis that EGF-activated ARNT signaling may control tumor cell proliferation and metastasis by up-regulating the expression of COX-2, CXCLs, PTX3 and IL-1 These factors may affect the microenvironment around tumors and determine the dissemination of metastatic cancer cells to the specific distant tissue by cross talking with metastatic niche, and link to drug resistance. Our long term goals have been to clarify: (a) whether ARNT governs the EGF-regulated the formation of breast cancer and cancer cell metastasis; (b) whether ARNT-stimulated secretion of cytokines in the microenvironments participates in cancer cell migration and invasion in normoxic conditions; (c) whether ARNT contributes to the development of the acquired chemoresistance and could be as a therapeutic target in breast cancer. It is apparent that EMT is no longer a phenomenon limited to explaining the migration of cells to sites of developing tissues and organs during embryogenesis. Without a doubt, cancer cells that acquire a more mesenchymal phenotype through EMT are more aggressive and resistant to conventional chemotherapy. Future anti-cancer approaches should take into account the status of EMT in individual cancers as reversal of EMT could leads to enhanced sensitivity of cancer cells to specific anti-cancer agents, including ErbB and its downstream targets inhibitors. We propose that ARNT may be a key downstream factor of ErbB signaling pathways to control EMT. Thus, creating ARNT inhibitors as chemotherapeutic drugs to treat cisplatin and gefitinib resistant tumors is an efficient way to improve cancer therapy.