Aim: Cytochrome P450s (CYP450) enzymes regulate inflammation and atherosclerosis and can affect carotid plaque stability in patients with ischemic stroke (IS). This study aimed to investigate the association of CYP450 genetic variants with CYP plasma metabolite levels and plaque stability in patients with IS.
Aim: Ischemic stroke (IS) is a multifactorial disease caused by environmental risk factors and genetic susceptibility. However, few studies have assessed whether gene -gene interactions among cytochrome P450 (CYP) pathway genes influence the risk of IS. The aim of the present study was to investigate the association of 10 variants of eight CYP pathway genes with IS and to determine whether these gene -gene interactions increase the risk of IS. Methods: Ten variants of eight CYP pathway genes were examined using mass spectrometry methods in 396 patients with IS and 378 controls. Gene -gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. Results: Apart fro m variant rs9333025, there were no significant differences in the genotype distributions of the other nine variants between the two groups using the single -locus analytical approach. However, the GMDR analysis showed a significant gene -gene interaction among rs17110453, rs751141, and rs9333025, which scored 10 for cross-validation consistency and nine for the sign test (p 0.011). Individual patients with the combination of 17110453CC, rs751141GG, and rs9333025GG had a significantly higher risk for IS than those with the combination of 17110453AA, rs751141AA, and rs9333025AA [odds ratio (OR) 2.86, 95% confidence interval (CI): 1.24 -7.26, p 0.004]. Logistic regression analysis showed that certain gene -gene interactions among rs17110453, rs751141, and rs9333025 predict a higher risk for IS (OR 2.36, 95% CI: 1.228 -5.297, p 0.005). Conclusion:The three-loci interaction may confer a higher risk for IS. The combinatorial analysis used in this study may be helpful to elucidate complex genetic risk factors for IS.
Background: AIB1 (SRC-3, NCoA3), a member of the p160/steroid receptor coactivators family, plays a critical role in cell growth and proliferation. In estrogen receptor-alpha positive (ER+) breast cancer (BC) cells, it coactivates estrogen- and additional transcription factors-dependent gene transcription, reducing the antagonistic activity of tamoxifen and resulting in tamoxifen resistance (TR). We have previously shown that BC patients whose tumors expressed high levels of both AIB1 and HER-2 had worse outcomes with tamoxifen therapy, suggesting that AIB1 may be an important diagnostic and therapeutic target. Our findings that knocking down AIB1 attenuates ER signaling and inhibits breast cancer cell growth further indicate that the manipulation of AIB1 level could be an approach to treating BC and overcoming TR. Recently, it has been shown that protein kinase C (PKC) isoforms phosphorylate AIB1 and prevent its proteasome-mediated degradation. The present study was carried out to test if the multi-targeted kinase and PKC inhibitor PKC412 (midostaurin) is capable of promoting degradation of AIB1, inhibiting BC cell growth, and promoting tamoxifen antagonistic activity. Methods: The ER+ MCF7, T47D, and ZR75-B BC cells and their tamoxifen-resistant derivatives (TR) were used. The Methylene Blue assay was employed to measure cell viability of BC cell lines after treatment with PKC412 or the combination of PKC412 with tamoxifen. To determine the impact of PKC412 on AIB1 and ER proteins and mRNA levels, we used immunoblotting and RT-qPCR, respectively. Results: PKC412 successfully inhibited the growth of MCF7, T47D, and ZR75-B cells, and their tamoxifen-resistant derivatives. Treatment with PKC412 depleted AIB1 protein and reduced the level of ER protein without significant alteration in AIB1 mRNA level. Consequently, ER signaling was disrupted, as reflected by decreased expression of ER target genes such as GREB1. PKC412 also enhanced tamoxifen's antagonistic activity in the parental cell lines and sensitized tamoxifen-resistant MCF7 and ZR75-B cells to tamoxifen. Conclusions: The results of this study suggest that the multi-targeted kinase and PKC inhibitor PKC412 can post-translationally destabilize AIB1 protein and ER, inhibiting BC cell growth and viability. PKC412 enhances tamoxifen's antagonistic activity on BC growth; furthermore, it sensitizes tamoxifen-resistant cells to tamoxifen. Thus, PKC412 is a promising agent to treat BC and, in combination with tamoxifen, to delay or overcome TR. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-03.
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