No abstract

Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. The transition from chemotherapy-responsive breast cancer cells to chemotherapy-resistant cancer cells is mainly accompanied by the increased expression of multidrug resistanceassociated proteins (MRPs). In this study, it was found that TAM-resistant MCF-7 (TAMR-MCF-7) cells expressed higher levels of MRP2 than control MCF-7 cells. Molecular analyses using MRP2 gene promoters supported the involvement of the pregnane X receptor (PXR) in MRP2 overexpression in TAMR-MCF-7 cells. Although CCAAT/enhancer-binding protein b was overexpressed continuously in TAMR-MCF-7 cells, this might not be responsible for the transcriptional activation of the MRP2 gene. In addition, the basal activities of phosphatidylinositol 3-kinase (PI3-kinase) were higher in the TAMR-MCF-7 cells than in the control cells. The inhibition of PI3-kinase significantly reduced both the PXR activity and MRP2 expression in TAMR-MCF-7 cells. Overall, MRP2 induction plays a role in the additional acquisition of chemotherapy resistance in TAM-resistant breast cancer.

Both the functional loss of p53 and the overexpression of aromatase are important for the progression of breast cancer in postmenopausal women. Here, we found that aromatase expression was up-regulated in primary cultures of mammary epithelial cells (p53 D5,6 MEC) isolated from mice with a defect in exons 5 and 6 of the p53 gene. Aromatase basal activity and expression levels were significantly increased in p53 D5,6 MEC when compared with wild-type MEC. Reporter gene activity in p53 D5,6 MEC transfected with the aromatase promoter or the cAMP-responsive element (CRE) minimal promoter was higher than wild-type MEC. p53 inactivation increased both Ser133-phosphorylated CRE-binding protein (CREB) and the nuclear accumulation of CREB. Inhibition of extracellular signal-regulated kinase (ERK) or Src tyrosine kinase blocked aromatase gene transactivation and CREB activation in the p53 D5,6 MEC. These results support the hypothesis that a genetic defect in the function of p53 enhances the expression of aromatase via ERK or Src activation in MEC, which suggests that aromatase expression is closely related to the p53 status in MEC.

tives are synthesized and evaluated for their ability to inhibit P-glycoprotein. Compound (I) shows a 3-fold increased inhibition compared with standard inhibitor verapamil. In addition, co-treatment of (I) and doxorubicin results in a remarkable increase in doxorubicin's antitumor effect and inhibition of DNA synthesis in the MCF-7/ADR cell lines. -(LEE*, K.; ROH, S. H.; XIA, Y.; KANG, K. W.; Bull. Korean Chem. Soc. 32 (2011) 10, 3666-3674, http://dx.