The human CD44 gene undergoes extensive alternative splicing of multiple variable exons positioned in a cassette in the middle of the gene. Expression of alternative exons is often restricted to ...certain tissues and could be associated with tumor progression and metastasis of several human malignancies, including breast cancer. Exon v4 contains multiple copies of a C/A-rich exon enhancer sequence required for optimal inclusion of the exon and binding to the nucleic acid-binding proteins YB-1 and human Tra2- beta 1. Here, we show that hTra2- beta 1, a member of the extended family of serine/arginine-rich (SR) splicing factors, enhances the in vivo inclusion of CD44 exons v4 and v5. It increased inclusion of exons v4 and v5 and acted synergistically with YB-1. Activation required the C/A-rich enhancer within exon v4. Several other SR proteins had none or only a slight effect on CD44 exon inclusion. In contrast, SC35 inhibited exon usage and antagonized the effects of Tra2 or YB-1. In a matched pair analysis of human breast cancers and their corresponding nonpathologic tissue controls, we found a significant induction of Tra2- beta 1 in invasive breast cancer, both on the RNA and protein levels. Together with our functional data, these results suggest an important role for Tra2- beta 1 in breast cancer. Induction of this splicing factor might be responsible for splicing of CD44 isoforms associated with tumor progression and metastasis. (Cancer Res 2006; 66(9): 4774-80)
Abstract
The human CD44 gene undergoes extensive alternative splicing of multiple variable exons positioned in a cassette in the middle of the gene. Expression of alternative exons is often ...restricted to certain tissues and could be associated with tumor progression and metastasis of several human malignancies, including breast cancer. Exon v4 contains multiple copies of a C/A-rich exon enhancer sequence required for optimal inclusion of the exon and binding to the nucleic acid–binding proteins YB-1 and human Tra2-β1. Here, we show that hTra2-β1, a member of the extended family of serine/arginine-rich (SR) splicing factors, enhances the in vivo inclusion of CD44 exons v4 and v5. It increased inclusion of exons v4 and v5 and acted synergistically with YB-1. Activation required the C/A-rich enhancer within exon v4. Several other SR proteins had none or only a slight effect on CD44 exon inclusion. In contrast, SC35 inhibited exon usage and antagonized the effects of Tra2 or YB-1. In a matched pair analysis of human breast cancers and their corresponding nonpathologic tissue controls, we found a significant induction of Tra2-β1 in invasive breast cancer, both on the RNA and protein levels. Together with our functional data, these results suggest an important role for Tra2-β1 in breast cancer. Induction of this splicing factor might be responsible for splicing of CD44 isoforms associated with tumor progression and metastasis. (Cancer Res 2006; 66(9): 4774-80)
Alternative splicing represents an important nuclear mechanism in the post-transcriptional regulation of gene expression, which is frequently altered during tumorigenesis. Previously, we have ...described marked changes in alternative splicing of the CD44 gene in ovarian and breast cancer. In the latter one we described also a specific induction of splicing factors during tumor development. Now we have focussed our studies on the expression profiles of splicing factors, including classical SR proteins, Tra2 and YB-1 in physiological and malignant ovarian tissues by RT-PCR and Western blot analysis. We detected changed expression pattern with higher levels of phosphorylated 30 kDa SR proteins as well as relatively high concentrations of hyperphosphorylated Tra2 protein isoforms in ovarian cancer. RT-PCR analysis revealed a marked induction of SC35 and ASF/SF2 as well as mRNA levels in malignant ovarian tissue. These results suggest gene-specific alterations of expression rather than a general induction of the splicing machinery. Together with previously performed functional studies of CD44 splicing these findings implicate that altered expression profiles of SR proteins, Tra2beta and YB-1 might be responsible for the known changes of alternative CD44 splicing in ovarian cancer.
The aim of this study was to evaluate the ultrasound (US) morphology of invasive lobular breast carcinomas (ILC) in comparison to that of invasive tumors of other histologic differentiation (TOD). ...Images of 406 breast lesions were included in this retrospective study. A total of 10 US criteria (shape, orientation, echogenicity, echo pattern, calcifications, margin, margin contour, lesion boundary, surrounding tissue and posterior acoustic features) were defined and determined. Tumors were stratified into ILC (n = 69) vs. TOD (n = 337). The correlation between the sonographically and pathologically measured size of the tumors was analyzed. Irregular shape was found in 88% of ILC vs. 67% of TOD (p < 0.001). Margins were indistinct in 94% of ILC compared to 76% of TOD (p = 0.001). Posterior shadowing was observed in 84% of ILC and 58% of TOD (p = 0.001). Irregular margin contour, hyper- or isoechoic pattern and architectural distortion were more frequent in ILC. Underestimation of tumor size by US was significantly more frequent in ILC (5.4 +/- 12.2 mm) than in TOD (1.4 +/- 12.0 mm) (p = 0.015). In summary, we found that histologic differentiation significantly influences ultrasonographic appearance of breast cancer. The underestimation of tumor size of ILC might compromise the operative strategy.
To evaluate the influence of distinct clinicopathological parameters on ultrasound criteria for ductal invasive breast cancer.
The hardcopy prints of 337 ductal invasive breast cancers were analyzed. ...Ten ultrasound criteria (shape, orientation, echogenicity, echo pattern, calcifications, margin, margin contour, lesion boundary, surrounding tissue, and posterior acoustic features) were defined and correlated to age, tumor size, axillary lymph node status, and histological grading in a multivariate analysis.
Tumors in women < or = 50 years displayed more often an indistinct margin (p = 0.003) and an enhanced/indifferent posterior ultrasound transmission (p = 0.008). Tumors in an advanced T-stage showed more frequently an irregular shape ( p = 0.006), an orientation parallel to the skin ( p = 0.01), hypoechogenicity ( p < 0.0001), and less often calcifications ( p = 0.002). A positive axillary lymph node status was significantly correlated to oval/round shape ( p = 0.004), hyper-/isoechogenicity ( p = 0.001), and a homogeneous echo pattern ( p = 0.002). Grading showed no correlation to the examined ultrasound criteria.
Breast ultrasound criteria, which are used to differentiate benign from malignant breast lesions, are influenced by age, size and lymph node status. These clinical conditions should be considered in the ultrasound diagnosis of breast lesions.
The human CD44 gene undergoes extensive alternative splicing of multiple variable exons positioned in a cassette in the middle of the gene. Expression of alternative exons is often restricted to ...certain tissues and could be associated with tumor progression and metastasis of several human malignancies, including breast cancer. Exon v4 contains multiple copies of a C/A-rich exon enhancer sequence required for optimal inclusion of the exon and binding to the nucleic acid-binding proteins YB-1 and human Tra2-beta1. Here, we show that hTra2-beta1, a member of the extended family of serine/arginine-rich (SR) splicing factors, enhances the in vivo inclusion of CD44 exons v4 and v5. It increased inclusion of exons v4 and v5 and acted synergistically with YB-1. Activation required the C/A-rich enhancer within exon v4. Several other SR proteins had none or only a slight effect on CD44 exon inclusion. In contrast, SC35 inhibited exon usage and antagonized the effects of Tra2 or YB-1. In a matched pair analysis of human breast cancers and their corresponding nonpathologic tissue controls, we found a significant induction of Tra2-beta1 in invasive breast cancer, both on the RNA and protein levels. Together with our functional data, these results suggest an important role for Tra2-beta1 in breast cancer. Induction of this splicing factor might be responsible for splicing of CD44 isoforms associated with tumor progression and metastasis.
The Advanced Breast Biopsy Instrumentation (ABBI) System is designed to excise nonpalpable breast lesions under stereotactic control. We report our experience with special regard to the histological ...evaluation of margins.
Breast biopsies using the ABBI system were performed on 101 patients with microcalcifications. In histologically-proven breast cancer, a re-excision was performed.
Malignant lesions were found in thirteen patients (3 CLIS, 5 DCIS, 5 invasive ductal carcinoma). The margins were positive in two specimens with DCIS. In subsequent lumpectomies one patient with invasive cancer had residual intraductal cancer. All the patients with DCIS had residual cancer, even those with negative margins of the ABBI-specimen. Only minor complications were observed with the ABBI procedure.
The ABBI system is a safe, minimally invasive stereotactic breast biopsy technique. It saves open biopsies in atypical hyperplasia and CLIS. In cases of DCIS or invasive cancer re-excision is inevitable.
We have examined Sondrestrom incoherent scatter radar observations of ionospheric plasma density and temperature distributions and measurements of F region ion drifts that were made during a prenoon ...pass of the Defense Meteorological Satellite Program (DMSP)-F7 satellite through the radar field of view. The spacecraft traversed a region of intense electron precipitation with a characteristic energy below approximately 200 eV. Particles with such low characteristic energies are believed to be directly or indirectly of magnetosheath origin. The precipitation region had a width about 2 deg invariant latitude and covered the low-latitude boundary layer (LLBL), the cusp, and the equatorward section of the plasma mantle (PM). The corotating radar observed a patch of enhanced electron density and elevated electron temperature in the F2 region between about 10.5 and 12 magnetic local time in the same invariant latitude range where DMSP-F7 detected the soft-electron flux. The ion drift pattern, also obtained by radar, shows that it is unlikely that the plasma patch was produced by solar radiation and advected into the radar field of view. We suggest that the radar observed modifications of the ionospheric plasma distribution, which resulted from direct entry of magnetosheath electrons into the magnetosphere and down to ionospheric altitudes. Model calculations of the ionospheric response to the observed electron precipitation support our interpretation. The spectral characteristics of the electron flux in the LLBL, cusp, and equatorward section of the PM were in this case too similar to allow to distinguish between them by using incoherent scatter radar measurements only.
