KPNA2 protein expression in invasive breast carcinoma and matched peritumoral ductal carcinoma in situ

Dankof, Anja; Fritzsche, Florian; Dahl, Edgar; Pahl, Stefan; Wild, Peter J.; Dietel, Manfred; Hartmann, Arndt; Kristiansen, Glen

doi:10.1007/s00428-007-0513-5

Cited by 51 publications

(49 citation statements)

References 18 publications

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“…In conclusion, our in vitro data complement the recently published prognostic impact of KPNA2 expression (Dahl et al, 2006;Dankof et al, 2007;Gluz et al, 2008) and support evidence that KPNA2 overexpression fosters the oncogenic properties of human breast cancer cells. Considering the biological function of KPNA2, possible molecular mechanisms behind these phenotypic alterations appear complex and remain to be deciphered.…”

Section: Discussionsupporting

confidence: 88%

“…Further gene expression studies revealed aberrant KPNA2 expression in premalignant and non-invasive ductal carcinomas in situ, indicating that this event occurs already in early stages of breast cancer development (Dankof et al, 2007;Klein et al, 2007). The prognostic significance of KPNA2 overexpression was associated with node-positive, highrisk breast cancer patients, who exhibited aggressive tumors with poor differentiation, negative hormone receptor status, as well as Her2/Neu, EGFR and p53 overexpression (Gluz et al, 2008).…”

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confidence: 94%

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Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

et al. 2011

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Tumorigenesis and tumor progression are associated with dysfunction of the nuclear transport machinery at the level of import and export receptors (karyopherins). Recent studies have shown that the nuclear import factor karyopherin-a2 (KPNA2) is a novel prognostic marker for poor prognosis in human breast cancer. Based on the well-defined hallmarks of cancer progression, we performed a detailed in vitro characterization of the phenotypic effects caused by KPNA2 overexpression and KPNA2 silencing in benign and malignant human breast cells. KPNA2 overexpression clearly increased proliferation of MCF7 tumor cells and further led to a reduction of cell-matrix adhesion in benign MCF10A cells, whereas cell migration was significantly increased (Po0.0001) in both tumor models. Remarkably, these individual effects of KPNA2 overexpression on proliferation, cell-matrix adhesion and migration resulted in an increased colony spreading of benign MCF10A breast cells and malignant MCF7 tumor cells (Po0.001), which is a hallmark of cancer progression. Conversely, RNA interference-mediated KPNA2 silencing caused a complete inhibition of MCF7 tumor cell proliferation and migration (Po0.0001). In addition, in these experiments apoptosis was increased (Po0.05) and formation of tumor cell colonies was reduced (Po0.01). Thus, KPNA2 overexpression provoked increased aggressiveness of malignant MCF7 breast tumor cells and induced a shift in benign MCF10A breast cells toward a malignant breast cancer phenotype. In conclusion, we demonstrate for the first time in experimental tumor models that forced KPNA2 expression drives malignant features relevant for breast cancer progression, while its silencing is required for the remission of those progressive phenotypes. This study gives clear evidence that KPNA2 acts as a novel oncogenic factor in human breast cancer, in vitro.

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Section: Discussionsupporting

confidence: 88%

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confidence: 94%

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

et al. 2011

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“…For negative controls, the primary antibody was omitted. The specificity of the commercial KPNA2 antibody has been thoroughly validated in former studies (11)(12)(13), and was further tested by using the human PCa cell lines PC3 and LNCaP. Cells were trypsinized and embedded in paraffin as a cell pellet.…”

Section: Immunohistochemical Assaymentioning

confidence: 99%

“…Further, analysis by immunohistochemistry showed that nuclear KPNA2 overexpression was significantly associated with shorter overall survival and recurrence-free survival (RFS). Nuclear KPNA2 expression was a highly significant, independent, and adverse risk factor for overall survival in several independent study cohorts (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

“…A novel candidate biomarker for tumor aggressiveness is the expression of karyopherin alpha 2 (KPNA2). We previously identified KPNA2 overexpression as a possible prognostic marker for breast cancer on mRNA and protein level (11)(12)(13). Twenty-four matched pairs of invasive ductal breast cancer and corresponding benign breast tissue were investigated by a combination of laser microdissection and gene expression profiling.…”

Section: Introductionmentioning

confidence: 99%

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KPNA2 Expression Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

Mortezavi

Hermanns

Seifert

et al. 2011

Clinical Cancer Research

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103

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Purpose: To analyze rates of expression of karyopherin alpha 2 (KPNA2) in different prostate tissues and to evaluate the prognostic properties for patients with primary prostate cancer.Experimental Design: Tissue microarrays (TMA) contained 798 formalin-fixed, paraffin-embedded prostate tissue cores from two different institutes of pathology. TMAs were stained immunohistochemically for KPNA2 and NBS1. SiRNA technologies were used to inhibit KPNA2 expression in vitro, and the effect of this inhibition on cellular viability was determined. Efficiency of knockdown experiments was determined by Western blot analysis.Results: KPNA2 expression was significantly upregulated in carcinomas of the prostate, especially in metastatic and castration-resistant prostate cancer samples. Positive nuclear KPNA2 immunoreactivity was identified as a novel predictor of biochemical recurrence after radical prostatectomy (n ¼ 348), and was independent of the well-established predictive factors preoperative PSA value, Gleason score, tumor stage, and surgical margin status. These results were validated by analyzing a second and independent prostate cancer cohort (n ¼ 330). Further, in vitro experiments showed that the cell proliferation and viability of PC3 cells was significantly reduced when KPNA2 expression was inhibited. KPNA2 knockdown did not induce PARP cleavage as marker for apoptosis. No significantly increased sub-G 1 fraction could be found by FACS analysis.Conclusions: KPNA2 is a novel independent prognostic marker for disease progression after radical prostatectomy. This allows to identify patients who need more aggressive treatment. It can moreover be speculated that patients not suited for surveillance regimens might be identified at initial biopsy by a positive KPNA2 immunohistochemistry.

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Circulating cell‐free messenger RNA enables non‐invasive pan‐tumour monitoring of melanoma therapy independent of the mutational genotype

Albrecht¹,

Höwner²,

Griewank³

et al. 2022

Clinical & Translational Med

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Background Plasma‐derived tumour‐specific cell‐free nucleic acids are increasingly utilized as a minimally invasive, real‐time biomarker approach in many solid tumours. Circulating tumour DNA of melanoma‐specific mutations is currently the best studied liquid biopsy biomarker for melanoma. However, the combination of hotspot genetic alterations covers only around 80% of all melanoma patients. Therefore, alternative approaches are needed to enable the follow‐up of all genotypes, including wild‐type. Methods We identified KPNA2 , DTL , BACE2 and DTYMK messenger RNA (mRNA) upregulated in melanoma versus nevi tissues by unsupervised data mining ( N = 175 melanoma, N = 20 normal skin, N = 6 benign nevi) and experimentally confirmed differential mRNA expression in vitro ( N = 18 melanoma, N = 8 benign nevi). Circulating cell‐free RNA (cfRNA) was analysed in 361 plasma samples (collected before and during therapy) from 100 melanoma patients and 18 healthy donors. Absolute cfRNA copies were quantified on droplet digital PCR. Results KPNA2 , DTL , BACE2 and DTYMK cfRNA demonstrated high diagnostic accuracy between melanoma patients’ and healthy donors’ plasma (AUC > 86%, p < .0001). cfRNA copies increased proportionally with increasing tumour burden independently of demographic variables and even remained elevated in individuals with radiological absence of disease. Re‐analysis of single‐cell transcriptomes revealed a pan‐tumour origin of cfRNA, including endothelial, cancer‐associated fibroblasts, macrophages and B cells beyond melanoma cells as cellular sources. Low baseline cfRNA levels were associated with significantly longer progression‐free survival (PFS) ( KPNA2 HR = .54, p = .0362; DTL HR = .60, p = .0349) and overall survival ( KPNA2 HR = .52, p = .0237; BACE2 HR = .55, p = .0419; DTYMK HR = .43, p = .0393). Lastly, we found that cfRNA copies significantly increased during therapy in non‐responders compared to responders regardless of therapy and mutational subtypes and that the increase of KPNA2 (HR = 1.73, p = .0441) and DTYMK (HR = 1.82, p = .018) cfRNA during therapy was predictive of shorter PFS. Conclusions In sum, we identified a new panel of cfRNAs for...

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KPNA2 protein expression in invasive breast carcinoma and matched peritumoral ductal carcinoma in situ

Cited by 51 publications

References 18 publications

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

KPNA2 Expression Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

Circulating cell‐free messenger RNA enables non‐invasive pan‐tumour monitoring of melanoma therapy independent of the mutational genotype

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