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BACKGROUND: Deletions of chromosome 10q23, including the PTEN (phosphatase and tensin homolog) locus, are known to occur in breast cancer, but systematic analyses of its clinical relevance are lacking. METHODS: We thus analyzed a tissue microarray (TMA) with 2,197 breast cancers by fluorescence in-situ hybridization (FISH) using a PTEN-specific probe. RESULTS: PTEN deletions were detected in 19% of no special type, 9% of lobular, 4% of tubular cancers and 46% in carcinomas with medullary features. 98.7% of deletions were heterozygous and only 1.3% were homozygous. PTEN deletion was significantly linked to advanced tumor stage (p=0.0054), high-grade (p<0.0001), high tumor cell proliferation (Ki67 Labeling Index; p<0.0001), and shortened overall survival (p=0.0090). PTEN deletions were inversely associated with features of luminal type breast cancers (ER/PR positivity; p<0.0001 each, and CCND1 amplification; p=0.0020). PTEN deletions were also strongly linked to amplification of genes involved in the PTEN/AKT pathway such as MYC (p=0.0430) and HER2 (p=0.0065). Remarkably the combined analysis of MYC, HER2, CCND1 and PTEN aberrations suggested that aberrations of multiple PTEN/AKT pathway genes have a strong additive effect on breast cancer prognosis. While cancers with one of these aberrations behaved only marginally different from cancers with none, disease outcome was markedly worse in cancers with two or more aberrations as compared to those with only one aberration (p=0.0002). In addition, the particularly poor prognosis of patients with HER2 amplification and PTEN deletions challenges the concept of PTEN deletions interfering with trastuzumab therapy. CONCLUSION: PTEN deletion occurs in a relevant fraction of breast cancers, and is linked to aggressive tumor behavior. Reduced PTEN function cooperates with MYC and HER2 activation in conferring aggressive phenotype to cancer cells.

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Deletions of chromosome 8p occur frequently in breast cancers, but analyses of its clinical relevance have been limited to small patient cohorts and provided controversial results. A tissue microarray with 2,197 breast cancers was thus analyzed by fluorescence in-situ hybridization using an 8p21 probe in combination with a centromere 8 reference probe. 8p deletions were found in 50% of carcinomas with no special type, 67% of papillary, 28% of tubular, 37% of lobular cancers and 56% of cancers with medullary features. Deletions were always heterozygous. 8p deletion was significantly linked to advanced tumor stage (P < 0.0001), high-grade (P < 0.0001), high tumor cell proliferation (Ki67 Labeling Index; P < 0.0001), and shortened overall survival (P < 0.0001). For example, 8p deletion was seen in 32% of 290 grade 1, 43% of 438 grade 2, and 65% of 427 grade 3 cancers. In addition, 8p deletions were strongly linked to amplification of MYC (P < 0.0001), HER2 (P < 0.0001), and CCND1 (p = 0.001), but inversely associated with ER receptor expression (p = 0.0001). Remarkably, 46.5% of 8p-deleted cancers harbored amplification of at least one of the analyzed genes as compared to 27.5% amplifications in 8p-non-deleted cancers (P < 0.0001). In conclusion, 8p deletion characterizes a subset of particularly aggressive breast cancers. As 8p deletions are easy to analyze, this feature appears to be highly suited for future DNA based prognostic breast cancer panels. The strong link of 8p deletion with various gene amplifications raises the possibility of a role for regulating genomic stability.

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Metastasis represents a major problem in the treatment of patients with advanced primary breast cancer. Both Transforming Growth Factor-Beta (TGF-ß) signaling and Plasminogen Activator (PA) components, urokinase-type Plasminogen Activator (uPA) and Plasminogen Activator Inhibitor-1 (PAI-1) represent a complex network crucial for such enhanced invasiveness of tumors and imply high prognostic/predictive and promising therapeutic potential. Therefore, protein expression of specific effector molecules comprising the main parts of the TGF-ß signaling pathway were determined in HOPE-fixed human tumor tissues through IHC (Scoring) using tissue microarray (TMA) technique and correlated with respective uPA and PAI-1 levels determined earlier in the same TMAs through optimized IHC and semi-quantitative image analysis. TGF-ß signaling was active in vast majority (96 %) of the tumor samples and 88 % of all cases were significantly correlated with established metastasis markers uPA and PAI-1. In addition, TGF-ß was also closely associated with tumor size, nodal status and two steroid hormone receptors. Consistent interrelationships between TGF-ß, PA components and additional tumor characteristics underline the superiority of such more comprising data with regards to confirming TGF-ß signaling as a promising target system to inhibit metastasis in advanced breast cancer.

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The determination of the invasion markers urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) has further improved the possibilities for individualized therapy of breast cancer. To date, quantitative measurement by ELISA, that needs large amounts of fresh, frozen material, is the only standardized procedure for diagnostic purposes. Therefore, the aim of this study was the establishment of a reliable alternative method based on immunohistochemistry (IHC) and image analysis requiring only small amounts of fixed tumor tissue. Protein expression of uPA and PAI-1 was analyzed in HOPE-fixed tumor samples using tissue microarrays (TMAs) and semiquantitative image analysis. The results of both methods were significantly correlated and risk assessment showed an overall concordance of 78% (83/107; high- and low-risk) and of 94% (74/79) regarding only high-risk patients. The data demonstrate that optimized IHC in combination with image analysis can provide adequate clinical significance compared to ELISA-derived determination of uPA and PAI-1.

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We reported on the results of 703 breast reduction operations performed by a modified technique after McKissock/Strömbeck. Altogether we operated in the last 10 years 360 patients (15-65 years; mean 32 years) at the Johanniter Hospital in Geesthacht. Only such patients were operated on for whom a medical necessity for reduction of the breast was established, such as orthopaedic problems etc. Complications in healing, especially of the nipple, the supporting parts of the nipple, and parenchyma were examined with these different variables: age of the patients, nicotine consumption, weight of tissue taken out, preoperative distance between nipple and jugulum, body weight of the patient in relation to normal weight, length of operation, loss of blood, and parenchymal histology. Life-endangering complications did not occur in any patient. Infections were seen in 2/360 patients (0.6%). All patients were given a perioperative antibiotic prophylactic, usually with Baypen (mezlocillin). Removable haematoma was seen in only 2/703 (0.3%). 100% necrosis of the nipple was seen in 4/703 reduced breast (0.6%), which agrees with Strömbeck's results (10). Other authors count up to 7.1% complete necrosis of the nipple (2n, 15). Nipple necrosis in part (1/3-2/3) was seen in 14/703 (1.8%) mammaplasty. Statistically highly significant correlations were found in all healing disturbances in relation to the amount of reduced tissue, distance of jugulum to nipple and adipositas. Patients with parenchymal lipomatosis had more complications in relation to other histological types (p < 0.05 and p < 0.01). Especially smoking patients showed a correlation to necrosis of the nipple (p < 0.05%), not to parenchymal necrosis. The duration of operation was not in any way connected with the healing complications. With these results it is easier to obtain the patient's informed consent by means of individual explanations of the operation and its risks.

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The colour doppler signals of the female breast showed significant differences between malignant and benign breast lesions according to the criteria defined as follows: Pattern of vessels in the tumour area Amount of vessels compared with the contralateral side Speed maximum of a tumour-supplying arteria in comparison with the contralateral side. We were able to characterise the above in 13 of 14 malignancies. 10 of 10 benign lesion were identified correctly. In European literature, with the exception of one study, a similarly high sensitivity concerning the diagnosis of malignant breast tumours was reported. As our results show the extreme politary of malignancy and benign lesion, we are publishing them in order to draw attention this method as early as possible.

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