MicroRNAs are an extensive family of ϳ22-nucleotide-long noncoding RNAs expressed in a wide range of eukaryotes, including humans, and they are important in development and disease. We found that microRNA Mir-17-5p has extensive complementarity to the mRNA of AIB1 (named for "amplified in breast cancer 1"). Cell culture experiments showed that AIB1 expression was downregulated by Mir-17-5p, primarily through translational inhibition. Expression of Mir-17-5p was low in breast cancer cell lines. We also found that downregulation of AIB1 by Mir-17-5p resulted in decreased estrogen receptor-mediated, as well as estrogen receptorindependent, gene expression and decreased proliferation of breast cancer cells. Mir-17-5p also completely abrogated the insulin-like growth factor 1-mediated, anchorage-independent growth of breast cancer cells. Our results reveal that Mir-17-5p has a role as a tumor suppressor in breast cancer cells.MicroRNAs (miRNAs) are genomically encoded, ϳ22-nucleotide-long noncoding RNAs found in many organisms. miRNAs are produced from primary RNA polymerase II transcripts by sequential processing in the nucleus and cytoplasm (26,27). Nuclear precursor RNAs are cleaved by the endonuclease Drosha in a "microprocessor complex" to release pre-miRNAs, which are 60-to 70-nucleotide-long imperfect hairpin structures (10,20,25). After being transported to the cytoplasm by exportin-5, pre-miRNAs are processed by the endonuclease DICER, generating ϳ22-nucleotide duplexes, one strand of which is the mature miRNA (34,55,56). miRNAs inhibit the translation of their respective RNA targets through imperfect base-pairing interactions, often with the 3Ј-untranslated regions (UTRs) of target mRNAs, or degrade their targets through perfect or near-perfect base pairing (1, 9). A single miRNA can regulate a number of genes, as shown by Lim et al. in an experimental model (29), and genetic studies in various organisms suggest that miRNAs have pivotal roles in development, cell death, proliferation, and disease (3,8,19,45).There is increasing evidence that miRNAs are mutated or differentially expressed in many types of cancer. The miRNAs Mir-15 and Mir-16 were found to be deleted in 68% of patients with chronic lymphocytic leukemia (5). Downregulation of Mir-143 and Mir-145 has been observed in colorectal cancer (38), and let-7 expression is often reduced in lung cancers with a poor prognosis (23, 49). In addition, increased expression of the precursor of Mir-155 has been detected in pediatric Burkitt lymphoma (13). Based on cancer-associated alterations in miRNA expression and the location of miRNAs at genomic regions often involved in cancers, it has been suggested that miRNAs act as tumor suppressors or oncogenes (6, 33). For example, Mir-17-5p, also known as Mir-91, is located on chromosome 13q31; this gene is amplified in childhood lymphoma (42,48). The genomic location of Mir-17-5p also undergoes loss of heterozygosity in different types of cancer, including breast cancer (12,30,47,51).The clinical and epidemiologic...

Platinum-based antitumor agents have been effective in the treatments of many human malignancies but the ultimate success of these agents is often compromised by development of drug resistance. One mechanism associated with resistance to platinum drugs is reduced intracellular accumulation owing to impaired drug intake, enhanced outward transport, or both. Mechanisms for transporting platinum drugs were not known until recent demonstrations that import and export transporters involved in maintenance copper homeostasis are also involved in the transport of these drugs. Ctr1, the major copper influx transporter, has been convincingly demonstrated to transport cisplatin and its analogues, carboplatin, and oxaliplatin. Evidence also suggests that the two copper efflux transporters ATP7A and ATP7B regulate the efflux of cisplatin. These observations are intriguing, because conventional thinking of the inorganic physiologic chemistry of cisplatin and copper is quite different. Hence, understanding the underlying mechanistic aspects of these transporters is critically important. While the mechanisms by which hCtr1, ATP7A and ATP7B transport copper ions have been studied extensively, very little is known about the mechanisms by which these transporters shuffle platinum-based antitumor agents. This review discusses the identification of copper transporters as platinum drug transporters, the structural-functional and mechanistic aspects of these transporters, the mechanisms that regulate their expression, and future research directions that may eventually lead to improved efficacy of platinum-based-based drugs in cancer chemotherapy through modulation of their transporters' activities.

Melanomas and other cancers that do not express argininosuccinate synthetase (AS), the rate-limiting enzyme for arginine biosynthesis, are sensitive to arginine depletion with pegylated arginine deiminase (ADI-PEG20). However, ADI resistance eventually develops in tumors due to AS upregulation. Although it has been shown that AS upregulation involves c-Myc, the underlying mechanisms remain unknown. Here we show that ADI-PEG20 activates Ras signaling and the effector ERK and PI3K/AKT/GSK-3β kinase cascades, resulting in phosphorylation and stabilization of c-Myc by attenuation of its ubiquitin-mediated protein degradation mechanism. Inhibition of the induced cell signaling pathways using PI3K/AKT inhibitors suppressed c-Myc induction and enhanced ADI-mediated cell killing. Notably, in an animal model of AS-negative melanoma, combination therapy using a PI3K inhibitor plus ADI-PEG20 yielded additive anti-tumor effects as compared with either agent alone. Taken together, our findings offer mechanistic insight into arginine deprivation metabolism and ADI resistance, and they illustrate how combining inhibitors of the Ras/ERK and PI3K/AKT signaling pathways may improve ADI-PEG20 anti-cancer responses.