Klaus Czerwenka

Differential gene expression profile in breast cancer-derived stromal fibroblasts.

BackgroundBreast cancer is characterized by malignant transformation of epithelial cells, but stromal cells also play an important role in tumorigenesis. While tumor-derived fibroblasts display unique phenotypic properties, it is unclear whether they also represent are a specific subpopulation.Materials and MethodsStromal fibroblasts deriving from malignant tissue of 10 women with invasive breast cancer, and from normal breast tissue of 10 women with benign breast disorders, were subjected to differential complementary DNA Microarray Analysis by using a 2,400 gene cDNA array. Individual gene expression pattern were confirmed by RT-PCR.ResultsIn a cDNA array that allows to analyze the differential gene expression of more than 2,400 genes, the mRNA expression of 135 genes were increased more than 2 fold in fibroblasts from malignant breast tumors. The majority of these genes encode tumor-promoting cytokines, transcription factors and cell-matrix associated proteins. The mRNA expression of 110 genes decreased to less than 0.5 fold. The remaining 2,155 genes were not significantly altered. RT-PCR performed on individual biopsies from breast cancer and normal breast tissues confirmed the validity of the pooled gene expression signature.ConclusionBreast cancer-derived stromal fibroblasts show a distinctive gene expression pattern that differentiates them from normal breast stroma. Our observation of increased expression of tumor promotion-associated genes even in the absence of adjacent malignant epithelium suggests that tumor stroma is comprised of a fibroblastic subpopulation that provides for a microenvironment which supports tumor growth and invasion.

Insulin-like growth factor-1 receptor (IGF-1R) expression does not predict for resistance to trastuzumab-based treatment in patients with Her-2/ neu overexpressing metastatic breast cancer

Purpose: Her-2/neu and the insulin-like growth factor-1 receptor (IGF-1R) share common postreceptor-signaling pathways, and pre-clinical models have implicated IGF-1R-signaling in resistance to treatment with the anti-Her-2/neu antibody trastuzumab. The present analysis was performed to evaluate the clinical relevance of IGF-1R expression within the context of trastuzumab-based therapy. Patients and methods: We performed immunohistochemical (IHC) analysis for IGF-1R expression in tumor specimens from 72 patients receiving trastuzumab-based treatment for Her-2/neu-overexpressing metastatic breast cancer at a single institution. IGF-1R status was evaluated using different cut-offs for positivity regarding staining intensity and staining pattern. IGF-1R positivity was then correlated with clinical patient and biological tumor characteristics and the clinical course of disease of patients under trastuzumab-based therapy. Results: No pattern or intensity of staining for IGF-1R correlated with any of the clinical or biological characteristics. Likewise, response, clinical benefit, progression-free and overall survival were independent of IGF-1R expression in both, univariate and multivariate analyses (all P>0.05). Conclusions: We conclude that IGF-1R expression is not a major predictor of the clinical efficacy of trastuzumab-based treatment in patients with Her-2/neu- overexpressing metastatic breast cancer.

Increased natural killer cell activity correlates with low or negative expression of the HER‐2/neu oncogene in patients with breast cancer

Background. Increased expression of the HER‐2/neu oncogene in breast cancer correlates with decreased estrogen receptor concentration and seems to be an important prognostic factor. The authors investigated whether there is a correlation between HER‐2/neu expression and immunologic parameters representing tumor defense in patients with breast cancer.

Differential expression pattern of estrogen receptors, aromatase, and sulfotransferase in breast cancer tissue and corresponding lymph node metastases

Patients with hormone receptor positive breast cancer who are treated with endocrine therapy generally have a good prognosis. However, resistance to hormonal therapy and progression occurs, and the reasons for this are manifold. It has been proposed that the local estrogenic environment has a role in the process of local invasion and progression. We have determined the expression pattern of estrogen receptor α, estrogen receptor β, and the epithelial and stromal expression of the estrogen-metabolizing enzymes aromatase and sulfotransferase by immunohistochemistry in tissue arrays, containing 50 paraffin-embedded sets of tissues obtained from breast cancer and from corresponding metastatic axillary lymph nodes of the same patients. We have found statistically significant higher estrogen receptors α and β expression in primary tumors than in corresponding lymph node metastases (p = 0.0004 and p = 0.003, respectively). Aromatase was also expressed more frequently in epithelial as well as in stromal cells of the malignant tumor when compared to according lymph node metastases (p = 0.08 and p = 0.12, respectively). While in lymph node metastases only estrogen receptor α and stromal aromatase expression were correlated (p = 0.01), significant associations were seen between the estrogen receptor β and stromal aromatase, and epithelial sulfotransferase (p = 0.0006 and p = 0.03, respectively) in the primary tumor. We hypothesize that the decreased expression of local estrogens by aromatase, in combination with a decreased expression of estrogen receptors α and β in lymphatic metastases, renders these metastases hormone insensitive and could contribute to the poor response to endocrine therapy that is often seen in nodal-positive tumors.

The role of fibroblast growth factor 2 in patients with uterine smooth muscle tumors: an immunohistochemical study

OBJECTIVE Fibroblast growth factor 2 (FGF-2) is considered to be a potent stimulator of angiogenesis and seems therefore to play an important role in the growth of tumors. We compared the immunohistochemical profile of FGF-2 in patients with uterine leiomyomas, smooth muscle tumors of uncertain malignant potential (STUMP) and leiomyosarcoma (LMS). Furthermore, we tried to clarify the prognostic role of FGF-2 in uterine leiomyosarcoma. STUDY DESIGN FGF-2 expression was investigated by immunohistochemistry from paraffin-embedded tissue in 26 patients with leiomyoma, in 24 cases with STUMP and in 21 patients with LMS. The immunohistochemical profile of these 3 tumor entities was compared and regarding LMS correlated with different clinicopathologic parameters. RESULTS FGF-2 was expressed in 85% of leiomyomas, in 88% of STUMP and in 57% of LMS. Significant differences regarding the frequency of FGF-2 expression were observed between leiomyoma and LMS as well as between STUMP and LMS (p<0.05). In uterine LMS FGF-2 expression was statistically more frequent in cases with high histological grade (p<0.05). Furthermore, FGF-2 positive tumors demonstrated a statistically significant higher rate of recurrence disease and tumor progression (p=0.005). Disease free as well as overall survival was significantly shortened in patients with FGF-2 positive compared to FGF-2 negative tumors (p<0.05). CONCLUSION The significant correlation between FGF-2 expression and high histological grade indicates that FGF-2 might work as a negative predictive factor. Higher rates of recurrence disease as well as shortened disease free and overall survival among FGF-2 positive LMS support the potential role as prognosticator for poor clinical outcome.