Abstract. Triple negative breast cancer (TNBC) has a poor outcome due to the lack of beneficial therapeutic targets. To clarify the molecular mechanisms involved in the carcinogenesis of TNBC and to identify target molecules for novel anticancer drugs, we analyzed the gene expression profiles of 30 TNBCs as well as 13 normal epithelial ductal cells that were purified by laser-microbeam microdissection. We identified 301 and 321 transcripts that were significantly upregulated and downregulated in TNBC, respectively. In particular, gene expression profile analyses of normal human vital organs allowed us to identify 104 cancer-specific genes, including those involved in breast carcinogenesis such as NEK2, PBK and MELK. Moreover, gene annotation enrichment analysis revealed prominent gene subsets involved in the cell cycle, especially mitosis. Therefore, we focused on cell cycle regulators, asp (abnormal spindle) homolog, microcephaly-associated (Drosophila) (ASPM) and centromere protein K (CENPK) as novel therapeutic targets for TNBC. Small-interfering RNA-mediated knockdown of their expression significantly attenuated TNBC cell viability due to G1 and G2/M cell cycle arrest. Our data will provide a better understanding of the carcinogenesis of TNBC and could contribute to the development of molecular targets as a treatment for TNBC patients.

No abstract

The acquisition of endocrine resistance is a common obstacle in endocrine therapy of patients with oestrogen receptor-α (ERα)-positive breast tumours. We previously demonstrated that the BIG3–PHB2 complex has a crucial role in the modulation of oestrogen/ERα signalling in breast cancer cells. Here we report a cell-permeable peptide inhibitor, called ERAP, that regulates multiple ERα-signalling pathways associated with tamoxifen resistance in breast cancer cells by inhibiting the interaction between BIG3 and PHB2. Intrinsic PHB2 released from BIG3 by ERAP directly binds to both nuclear- and membrane-associated ERα, which leads to the inhibition of multiple ERα-signalling pathways, including genomic and non-genomic ERα activation and ERα phosphorylation, and the growth of ERα-positive breast cancer cells both in vitro and in vivo. More importantly, ERAP treatment suppresses tamoxifen resistance and enhances tamoxifen responsiveness in ERα-positive breast cancer cells. These findings suggest inhibiting the interaction between BIG3 and PHB2 may be a new therapeutic strategy for the treatment of luminal-type breast cancer.

These results indicate that candesartan cilexetil shows potent and long-term preventive effects against the progression of previously developed renal injury.

Studies of renal cell carcinoma (RCC) have led to the development of new molecular-targeted drugs but its oncogenic origins remain poorly understood. Here, we report the identification and critical roles in renal carcinogenesis for DDX31, a novel nucleolar protein upregulated in the vast majority of human RCC. Immunohistochemical overexpression of DDX31 was an independent prognostic factor for patients with RCC. RNA interference (RNAi)-mediated attenuation of DDX31 in RCC cells significantly suppressed outgrowth, whereas ectopic DDX31 overexpression in human 293 kidney cells drove their proliferation. Endogenous DDX31 interacted and colocalized with nucleophosmin (NPM1) in the nucleoli of RCC cells, and attenuation of DDX31 or NPM1 expression decreased pre-ribosomal RNA biogenesis. Notably, in DDX31-attenuated cells, NPM1 was translocated from nucleoli to the nucleoplasm or cytoplasm where it bound to HDM2. As a result, HDM2 binding to p53 was reduced, causing p53 stablization with concomitant G 1 phase cell-cycle arrest and apoptosis. Taken together, our findings define a mechanism through which control of the DDX31-NPM1 complex is likely to play critical roles in renal carcinogenesis. Cancer Res; 72(22); 5867-77. Ó2012 AACR.

Fibrosis of the lung constitutes a major clinical challenge and novel therapies are required to alleviate the associated morbidity and mortality. Investigating the antifibrotic efficacy of drugs that are already in clinical practice offers an efficient strategy to identify new therapies. The phosphodiesterase 4 (PDE4) inhibitors, approved for the treatment of chronic obstructive pulmonary disease, harbor therapeutic potential for pulmonary fibrosis by augmenting the activity of endogenous antifibrotic mediators that signal through cyclic AMP. In this study, we tested the efficacy of several PDE4 inhibitors including a novel compound (Compound 1) in a murine model of lung fibrosis that results from a targeted type II alveolar epithelial cell injury. We also compared the antifibrotic activity of PDE4 inhibition to the two therapies that are FDA‐approved for idiopathic pulmonary fibrosis (pirfenidone and nintedanib). We found that both preventative (day 0–21) and therapeutic (day 11–21) dosing regimens of the PDE4 inhibitors significantly ameliorated the weight loss and lung collagen accumulation that are the sequelae of targeted epithelial cell damage. In a therapeutic protocol, the reduction in lung fibrosis with PDE4 inhibitor administration was equivalent to pirfenidone and nintedanib. Treatment with this class of drugs also resulted in a decrease in plasma surfactant protein D concentration, a reduction in the plasma levels of several chemokines implicated in lung fibrosis, and an in vitro inhibition of fibroblast profibrotic gene expression. These results motivate further investigation of PDE4 inhibition as a treatment for patients with fibrotic lung disease.

Food thickening agents are used to aid the administration of medicine to elderly patients with dysphagia. Magnesium oxide tablets are sometimes administered with food thickening agents. Non-disintegration and disintegration delay of these tablets in the body are problems associated with food thickening agent use. However, the appropriate usage of food thickening agents for administering tablets is not established. Here, the reasons for the non-disintegration of magnesium oxide tablets administered with food thickeners and appropriate usage of food thickeners were examined using a disintegration test of newly opened and moisture-absorbed magnesium oxide tablets. Immersion of magnesium oxide tablets for 10 and 30 min in xanthan and guar gum-based food thickening agents caused disintegration delay and non-disintegration in the first fluid (pH 1.2). However, tablets immersed for 1 min quickly disintegrated. The disintegration of xanthan gum-based food thickening agents was faster than guar gum-based food thickening agents. Moisture absorption by magnesium oxide tablets caused a significant delay in their disintegration in water. The tablets that absorbed moisture disintegrated within 1 min in the first fluid, even when immersed in food thickening agents for a short time. Overall, a short immersion of magnesium oxide tablets in food thickening agents can avoid non-disintegration.

In mammals, 10 isoforms of fatty acid-binding protein (FABP) are expressed in various tissues. To understand the role of multiple FABP isoforms, we have quantitatively examined the transcript levels of individual FABP isoforms in each of various tissues by Northern blotting using synthesized RNAs corresponding to the mRNA of each isoform as external standards. As a result, absolute transcript levels of individual FABP isoforms expressed in each tissue were successfully determined. The 10 FABP isoforms were classified into three categories: (1) isoforms FABP7 and 12 were not markedly expressed in any tissue examined; (2) isoforms showing certain transcript levels in multiple tissues; and (3) isoforms FABP6, 8, and 9, expressed at certain levels in one particular tissue. Based on the expression profiles of the isoforms, individual tissues were also classified into three groups: (1) tissues in which high-level expression of FABP isoforms was not observed, (2) tissues in which multiple FABP isoforms were expressed at certain levels, and (3) tissues in which a single FABP isoform was dominantly expressed at a certain level. These results give a better understanding of the meaning of the presence of multiple FABP isoforms in mammals.