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Background: Prostate cancer shows considerable heterogeneity in disease progression and we propose that markers expressed in tumour stroma may be reliable predictors of aggressive tumour subtypes. Methods: We have used Kaplan–Meier, univariate and multivariate analysis to correlate the expression of Asporin (ASPN) mRNA and protein with prostate cancer progression in independent cohorts. We used immunohistochemistry and H scoring to document stromal localisation of ASPN in a tissue microarray and mouse prostate cancer model, and correlated expression with reactive stroma, defined using Masson Trichrome staining. We used cell cultures of primary prostate cancer fibroblasts treated with serum-free conditioned media from prostate cancer cell lines to examine regulation of ASPN mRNA in tumour stromal cells. Results: We observed increased expression of ASPN mRNA in a data set derived from benign vs tumour microdissected tissue, and a correlation with biochemical recurrence using Kaplan–Meier and Cox proportional hazard analysis. ASPN protein localised to tumour stroma and elevated expression of ASPN was correlated with decreased time to biochemical recurrence, in a cohort of 326 patients with a median follow up of 9.6 years. Univariate and multivariate analysis demonstrated that ASPN was correlated with progression, as were Gleason score, and clinical stage. Additionally, ASPN expression correlated with the presence of reactive stroma, suggesting that it may be a stromal marker expressed in response to the presence of tumour cells and particularly with aggressive tumour subtypes. We observed expression of ASPN in the stroma of tumours induced by p53 inhibition in a mouse model of prostate cancer, and correlation with neuroendocrine marker expression. Finally, we demonstrated that ASPN transcript expression in normal and cancer fibroblasts was regulated by conditioned media derived from the PC3, but not LNCaP, prostate cancer cell lines. Conclusions: Our results suggest that ASPN is a stromally expressed biomarker that correlates with disease progression, and is observed in reactive stroma. ASPN expression in stroma may be part of a stromal response to aggressive tumour subtypes.

HINTERGRUND: Stromale Fibroblasten beeinflussen Tumorwachstum und -progression. Gegenstand der vorliegenden Arbeit war die Evaluation der zwei Aldo-Keto-Reduktasen AKR1C1 und AKR1C2 in Stromalfibroblasten und Karzinomzellen als prognostische Faktoren bei primärem menschlichen Brustkrebs. Sie sind am intratumoralen Progesteronstoffwechsel beteiligt. METHODEN: Die Immunhistochemie wurde an Gewebemikroarrays aus 504 Kernbiopsien von Brustkrebspatientinnen durchgeführt. Primäre Endpunkte waren das krankheitsfreie (DFS) und das Gesamtüberleben (OS). ERGEBNISSE: AKR1C1 und AKR1C2 Expression in Fibroblasten und Tumorzellen korreliert mit günstigen Tumoreigenschaften, wie z.B. kleine Tumorgröße und negativer Lymphknotenstatus. In der univariaten Analyse korrelierte die AKR1C1-Expression in Karzinomzellen positiv mit DFS und OS; die AKR1C2-Expression in Fibroblasten und Tumorzellen zeigte ebenfalls eine positive Korrelation mit DFS und OS. In der multivariaten Analyse war die AKR1C1-Expression in Karzinomzellen ein unabhängiger prognostischer Marker. FAZIT: Es ist davon auszugehen, dass unsere Beobachtungen auf die unabhängige regulatorische Funktion von AKR1C1/2 im Progesteronstoffwechsel zurückzuführen sind und damit die Grundlage für neue hormonbasierte Therapieoptionen für Brustkrebspatientinnen unabhängig vom klassischen Hormonrezeptorstatus bilden. BACKGROUND: Stromal fibroblasts influence tumor growth and progression. We evaluated two aldo-keto reductases, AKR1C1 and AKR1C2, in stromal fibroblasts and carcinoma cells as prognostic factors in primary human breast cancer. They are involved in intratumoral progesterone metabolism. METHODS: Immunohistochemistry was performed on tissue microarrays from 504 core biopsies from breast cancer patients. Primary endpoints were disease-free (DFS) and overall (OS) survival. RESULTS: AKR1C1 and AKR1C2 expression in fibroblasts and tumor cells correlated with favorable tumor characteristics, such as small tumor size and negative nodal status. In univariate analysis, AKR1C1 expression in carcinoma cells correlated positively with DFS und OS; AKR1C2 expression in both fibroblasts and tumor cells also showed a positive correlation with DFS and OS. In multivariate analysis, AKR1C1 expression in carcinoma cells was an independent prognostic marker. CONCLUSION: It can be assumed that our observations are due to the independent regulatory function of AKR1C1/2 in progesterone metabolism and therefore provide a basis for new hormone-based therapy options for breast cancer patients, independent of classic hormone receptor status.