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Christian F Singer
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Gernot Hudelist
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Wolfgang Lamm
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Ruth Mueller
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Klaus Czerwenka
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Ernst Kubista
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Tyrosine kinase (TK) inhibition has been identified as a promising strategy in the treatment of human malignancies and several synthetic inhibitors have been developed. While the selective blockage of specific TKs is highly effective in vitro, clinical results have been less impressive. It has been suggested that the simultaneous inhibition of multiple TKs might lead to more favorable therapeutic results in vivo. We have therefore performed a systematic analysis of intratumoral TK expression in order to identify potential targets for a simultaneous kinase inhibition. To this end, we have analyzed the protein expression of membrane-associated epidermal growth factor receptor (EGF-R), Her-2/neu, platelet-derived growth factor receptor (PDGF-R), insulin-like growth factor receptor (IGF-R), c-Kit and of cytoplasmatic c-Abl in 500 human tumors of epithelial, stromal and mesenchymal origin by immunohistochemistry, and found a distinct pattern of kinase expression: EGF-R, PDGF-R and c-Abl were expressed in the majority of malignant tumors, whereas c-Kit, Her-2/neu and IGF-R protein expression was considerably less frequent. Overall, the EGF-R protein expression was correlated with PDGF-R, c-Kit and c-Abl immunoreactivity (P = 0.003, P = 0.001 and P < 0.001, respectively). c-Abl was co-expressed with IGF-R and PDGF-R (P = 0.003 and P < 0.001, respectively). Kinase co-expression was also seen in tumor subgroups and was particularly significant in breast cancer where IGF-R protein was expressed together with PDGF-R and c-Abl (P = 0.003 and P = 0.004, respectively), and in colon cancer where PDGF-R was correlated with EGF-R (P < 0.001). With the exception of Her-2/neu expression and age, intra-tumoral TK expression was not associated with parameters such as grading or histological subtypes. Taken together, we have found a specific pattern of kinase co-expression and have identified several potential targets for a tumor-specific multimodal TK inhibition.

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Christian F Singer
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Anneliese Fink-Retter
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Daphne Gschwantler-Kaulich
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Theresia Thalhammer
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Gernot Hudelist
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Ruth Mueller
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Klaus Czerwenka
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Ernst Kubista
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The suppression of local estrogens levels is of key importance in the treatment of ER-positive breast cancer. Essentially all endocrine strategies act by either suppressing estrogen formation or competitively inhibiting receptor-binding in tumor cells. Nevertheless, little is still known about the local expression of aromatase and sulfotransferase which are the key modulators of intra-tumoral estrogen levels. We have performed immunohistochemostry to investigate the expression of aromatase and sulfotransferase in 42 samples obtained directly from malignant breast tumors, and compared it to biopsies obtained from uninvolved tissue in the vicinity of the invasion front, and to distant breast tissue. We found that aromatase was equally detectable in both tumor epithelial and stroma, but was mostly epithelial in non-malignant tissues (P = 0.00008, Fisher’s exact test). Also, aromatase protein expression was significantly more common in tumoral stroma when compared with peritumoral and distant breast stroma (P = 0.00005, and P < 0.00001 respectively). With the notable exception of cystosarcoma phylloides, sulfotransferase protein was detectable only in epithelial tissues, regardless of the location within the diseased breast. However, epithelial sulfotransferase was correlated with epithelial aromatase (r = 0.35461, P = 0.0009, Spearman’s ρ test) and with the epithelial ER status (r = 0.29313, P = 0.005). We have demonstrated a differential aromatase and sulfotransferase protein expression pattern that is dependent on the spatial relation to a malignant breast tumor. Our results indicate a net increase in intratumoral active estrogen levels through increased stromal aromatization, while physiological local inactivation by sulfotransferase activity remains essentially unchanged.

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Christian F Singer Division of Special Gynecology, Division of Oncology, Division of Gynecopathology, Department of Obstetrics and Gynecology

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Gernot Hudelist Division of Special Gynecology, Division of Oncology, Division of Gynecopathology, Department of Obstetrics and Gynecology

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Eva-Maria Fuchs Division of Special Gynecology, Division of Oncology, Division of Gynecopathology, Department of Obstetrics and Gynecology

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Wolfgang Köstler Division of Special Gynecology, Division of Oncology, Division of Gynecopathology, Department of Obstetrics and Gynecology

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Anneliese Fink-Retter Division of Special Gynecology, Division of Oncology, Division of Gynecopathology, Department of Obstetrics and Gynecology

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Daphne Gschwantler-Kaulich Division of Special Gynecology, Division of Oncology, Division of Gynecopathology, Department of Obstetrics and Gynecology

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Michael Gnant Division of Special Gynecology, Division of Oncology, Division of Gynecopathology, Department of Obstetrics and Gynecology

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Wolfgang Lamm Division of Special Gynecology, Division of Oncology, Division of Gynecopathology, Department of Obstetrics and Gynecology

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Margarethe Rudas Division of Special Gynecology, Division of Oncology, Division of Gynecopathology, Department of Obstetrics and Gynecology

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Klaus Czerwenka Division of Special Gynecology, Division of Oncology, Division of Gynecopathology, Department of Obstetrics and Gynecology

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Ernst Kubista Division of Special Gynecology, Division of Oncology, Division of Gynecopathology, Department of Obstetrics and Gynecology

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ERBB2 amplification and consecutive overexpression is a predictor for poor prognosis in breast cancer patients. In addition, incomplete resection of ERBB2-overexpressing tumors leads to increased proliferation of residual breast cancer cells. While the local release of cytokines is thought to be responsible for the malignant behavior of remaining tumor tissue, the exact mechanism is still unknown. We have analyzed epidermal growth factor receptor (EGFR), activated (p)EGFR, and activated (p)ERBB2 protein expression in ERBB2-overexpressing and in non-ERBB2-overexpressing tumors from patients who underwent breast surgery and consecutive re-excision for involved margins, and compared expression levels by immunohistochemistry. While overall ERBB2 protein expression in the initial and the re-excised sample were comparable, we observed an increase in pERBB2 in ductal carcinomas in situ in both, ERBB2-overexpressing (16/21 vs 24/24; P=0.018, χ 2 test) and non-ERBB2-overexpressing tumors (3/28 vs 5/12; P=0.025, χ 2 test). pERBB2 was not increased in invasive tumors, regardless on whether the samples had been taken from a ERBB2-overexpressing (9/25 vs 6/17; P=0.261, χ 2 test) or a non-ERBB2-overexpressing tumor (1/27 vs 0/8; P=0.581, χ 2 test). EGFR expression was only detected in 1/47 ERBB2-overexpressing primary tumors and 2/48 non-ERBB2-overexpressing tumors, and was undetectable in re-excised specimen. Taken together, we have demonstrated an increase in ERBB2 receptor activation in incompletely resected preinvasive breast cancer. We hypothesize that receptor phosphorylation is caused by growth factor stimulation in response to intraoperative tissue damage, and perioperative inhibition of specific cytokines could become a promising therapeutic strategy.

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