Nuclear karyopherin α2 expression predicts poor survival in patients with advanced breast cancer irrespective of treatment intensity

West German Study Group, Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany.
International Journal of Cancer (Impact Factor: 5.09). 09/2008; 123(6):1433-8. DOI: 10.1002/ijc.23628
Source: PubMed


Intensive lymph node involvement indicates poor prognosis in breast cancer patients. The significance of other molecular prognostic factors in this subgroup is unclear. Karyopherin alpha2 (KPNA2) has been reported as an important factor of tumorgenesis and progression of breast cancer. The aim of present study was to evaluate the impact of KPNA2 expression on prognosis of patients with high risk breast cancer (HRBC) and response intensive chemotherapy within the randomized WSG-AM-01 trial. KPNA2 nuclear expression (>10% vs. <10% of nuclei) was measured by immunohistochemistry on tissue arrays of 191 patients randomized to tandem high dose vs. conventional dose-dense chemotherapy in HRBC with >9 positive lymph nodes and correlated with clinical outcome (median follow-up of 63.3 months) by Kaplan-Meier and multivariate Cox hazard model analysis, including, molecular subtypes determined by k-clustering (k = 5). KPNA2 overexpression (n = 74, 39%) significantly correlated with shorter event-free and overall survival (OS) in both therapy arms by univariate analysis. Multivariate analysis showed that the overexpression of KPNA2 was an independent prognostic factor of decreased OS HR = 1.86 [95% CI: 1.07-3.23, p = 0.03]. This predictive value was independent of basal-like/Her-2/neu subtypes, significantly associated with KPNA2 and was addressed particularly to G2 tumors. Our data suggest the use of KPNA2 nuclear expression as novel prognostic marker in node-positive patients, especially in determination of G2 tumors in 2 subgroups of different prognosis. KPNA2 expression may be also considered as a marker for global chemoresistance, which can not be overcome by conventional dose-modification of chemotherapy in advanced breast cancer.

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Available from: Andreas Gaumann
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    • "Previous reports have demonstrated KPNA2 overexpression in various tumors cells in vitro and in vivo; elevated KPNA2 and KPNB1 expression in cancer cells correlates with altered transcriptional regulation associated with deregulated E2F/Rb activities [26]. Some studies have indicated that higher KPNA2 expression in tumor cell nuclei shortens patient survival, although the mechanisms and precise roles of KPNA2 in the tumor cells remained unclear [16], [17]. Researchers also hypothesized that KPNA2-mediated nuclear transport of proteins necessary for maintaining cell proliferation, such as transcription factors, promote tumor cell growth. "
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    ABSTRACT: Karyopherin proteins mediate nucleocytoplasmic trafficking and are critical for protein and RNA subcellular localization. Recent studies suggest KPNA2 expression is induced in tumor cells and is strongly associated with prognosis, although the precise roles and mechanisms of KPNA2 overexpression in proliferative disorders have not been defined. We found that KPNA2 expression is induced in various proliferative disorders of the skin such as psoriasis, Bowen's disease, actinic keratosis, squamous cell carcinoma, Paget's disease, Merkel cell carcinoma, and mycosis fungoides. siRNA-mediated KPNA suppression revealed that KPNA2 is essential for significant suppression of HaCaT proliferation under starvation conditions. Ribosomal RNA transcription and protein synthesis were suppressed by starvation combined with knockdown of KPNA (including KPNA2) expression. KPNA2 localized to the nucleolus and interacted with proteins associated with mRNA processing, ribonucleoprotein complex biogenesis, chromatin modification, and transcription, as demonstrated by tandem affinity purification and mass spectrometry. KPNA2 may be an important promoter of ribosomal RNA and protein synthesis in tumor cells.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "In addition, many recent studies have identified high Kpnα2 in tumour tissue, suggesting that the upregulation of Kpnα2 associates with cancer development. Such cancers include melanoma [6], breast cancer [7]; [8], oesophageal cancer [9], ovarian cancer [10], non-small cell lung cancer [11], prostate cancer [12], bladder cancer [13] and liver cancer [14]. Interestingly, Wang et al. [11] showed that Kpnα2 is secreted into the serum, suggesting it has potential clinical usefulness as a cancer biomarker. "
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    ABSTRACT: The Karyopherin superfamily comprises nuclear transport proteins, involved in the shuttling of certain cargo proteins into and out of the nucleus. Karyopherin β1 (Kpnβ1) and Karyopherin α2 (Kpnα2) are importin proteins, which work in concert to transport their cargo into the nucleus. We previously identified increased expression of Kpnβ1 and Kpnα2 in cervical tumours compared to normal epithelium and in transformed cells compared to their normal counterparts. This study therefore aimed to identify the transcription regulatory mechanisms associated with high Kpnβ1 and Kpnα2 levels in cancer cells. Kpnβ1 (-2013 to +100) and Kpnα2 (-1900 to +69) promoter fragments were separately cloned into the reporter vector, pGL3-basic, and luciferase assays revealed both as significantly more active in cancer and transformed cells compared to normal. A series of deletion constructs identified the -637 to -271 Kpnβ1 and -180 to -24 Kpnα2 promoter regions as responsible for the differential promoter activity, and a number of highly conserved E2F binding sites were identified within these regions. Mutation analysis confirmed the requirement of E2F sites for promoter activity, and ChIP analysis confirmed E2F2/Dp1 binding to the Kpnβ1 and Kpnα2 promoters in vivo. Dp1 inhibition resulted in decreased levels of the respective proteins, confirming the role of E2F in the overexpression of Kpnβ1 and Kpnα2 proteins in cancer. E2F activity is known to be deregulated in cervical cancer cells due to the inhibition of its repressor, Rb, by HPV E7. The inhibition of E7 using siRNA resulted in decreased Kpnβ1 and Kpnα2 promoter activities, as did the overexpression of Rb. In conclusion, this study is a first to show that elevated Kpnβ1 and Kpnα2 expression in cancer cells correlates with altered transcriptional regulation associated with deregulated E2F/Rb activities.
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    ABSTRACT: During the past decade, a new dynamic perspective of vitamin D receptor (VDR) and retinoid X receptor (RXR) functions has emerged. The ability to monitor receptor movement in living cells by fluorescent techniques in real time has led to the realization that VDR, RXR, and most other nuclear receptors (NRs) and transcription factors constantly shuttle between the cytoplasm and the nucleus as well as between subnuclear compartments, and revealed the transient nature of receptor–DNA interactions. In this review, the significance of receptor trafficking is first highlighted, along with diseases associated with abnormal receptor localization. The significance of spatial and temporal control of transcription for the regulation of cell growth and differentiation is emphasized. Next, our current knowledge of the nuclear import and export machinery is summarized. Regulation of NR transport is discussed at the level of the receptor (nuclear localization sequence and nuclear export sequence modifications), at the level of import and export receptor expression, and at the level of signal-dependent changes in nuclear pore complex conformation. An understanding of how nuclear architecture and intranuclear NR mobility contribute to gene regulation concludes the review of the general aspects of NR trafficking. Then, information specific for VDR and RXR import, export, and intranuclear trafficking is presented in detail. Conclusions emphasize that understanding the spatial and temporal aspects of VDR functions is important, and express hope that rapid initial progress in this area will not be halted by economic and ideological pressure.
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