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Cytokines are and may be used as therapeutic targets in cancer therapy. In breast cancer, interleukin (IL)-6 is associated with different features of tumor biology like metastasis, certain stages, and decreased survival. It is now an established fact that signaling via the soluble IL-6 receptor (sIL-6R) («transsignaling») is an important process in the IL-6 machinery.In this mini-review, we discover that published knowledge about sIL-6R serum levels in breast cancer patients is sparse and, furthermore, most in vitro data merely show that tumor cells produce the sIL-6R endogenously.Therefore, a lot of research is still necessary to analyze the significance of the sIL-6R and therefore the transsignaling process in breast tumors. More knowledge about the sIL-6R in breast cancer would give insights into its putative role as blood marker of active tumor disease. Secondly, the sIL-6R may be useful in breast cancer as a new therapeutic pathway. If, as suggested by the literature, IL-6 mediates the aggressiveness and the growth of breast tumors, elevated circulating levels of IL-6 and its receptor may identify patients for whom the IL-6 complex is a therapeutic target.In der Krebstherapie stellen Zytokine therapeutische Angriffsziele, sogenannte Targets, dar. Beim Mammakarzinom ist ein hoher Interleukin (IL)-6-Gehalt mit verschiedenen Tumorcharakteristika wie z.B. Metastasierung, bestimmten Stadien und vermindertem Überleben assoziiert. In der Zwischenzeit hat sich herausgestellt, dass die Signalweiterleitung über den löslichen IL-6-Rezeptor (sIL-6R) (“Transsignaling”) von großer Bedeutung innerhalb des IL-6-Geschehens ist.In diesem Mini-Review stellen wir fest, dass das publizierte Wissen über den Serumgehalt an sIL-6R bei Mammakarzinompatienten lückenhaft ist. Des Weiteren zeigen publizierte In-vitro-Daten lediglich die Tatsache, dass Tumorzellen selber den sIL-6R produzieren.Aus diesem Grunde erscheint es uns notwendig herauszufinden, welche Bedeutung der sIL-6R, und damit einhergehend der Transsignaling-Prozess, beim Mammakarzinom hat. Ein breiteres Wissen über den sIL-6R beim Brustkrebs könnte seine Rolle als eventueller Marker des aktiven Tumorgeschehens beleuchten und eine neue therapeutische Möglichkeit darstellen, zumindest für diejenigen Patienten, deren Serumgehalte an IL-6 und/oder sIL-6R erhöht sind.

Besides hepatic P450 (cytochrome P450) metabolism, there is increasing interest in the possibility of intratumoral activation of oxazaphosphorines by P450. Therefore, we investigated the expression of P450 (CYP2C8, CYP2C9, CYP2C18, and CYP2C19) by RT (reverse transcriptase)-polymerase chain reaction (PCR) and of CYP2C9 by Western blotting in 10 different breast tumor samples. Since P450 may be down regulated by interleukin (IL) IL-6, the receptor (R) for IL-6 was analyzed by RT-PCR and IL-6 in supernatants was calculated from ELISA data. None of the breast tumors was positive for CYP2C18 and CYP2C19 mRNA, whereas CYP2C8 and CYP2C9 were detected in all 10 breast tumors. Correspondingly, all breast tumors tested (9 of 10) revealed low, but nevertheless positive, staining of the CYP2C9 protein. All 10 samples were positive for the IL-6 receptor mRNA. ELISA measurement of IL-6 cytokine in supernatants revealed that all measured samples (8 of 10) were producing IL-6, the amounts ranging from 0.004 to 3.1 ng/g(tumor tissue). In summary, we have demonstrated that tumors of the breast express two out of four members of the CYP2C family, indicating that activation of such prodrugs as oxazaphosphorines may take place intratumorally. The presence of the IL-6 receptor and of IL-6 cytokine, which is produced in an autocrine manner, opens up the possibility that the well-known down regulating effect of IL-6 also takes place in breast tumors and might explain the weak or even absent expression of different CYP2C members.

Ifosfamide is a prodrug that requires bioactivation by cytochrome P450 for antitumour activity. Up to now, little is known, to what extent in addition to the liver the ifosfamide metabolism may occur intratumorally. For this purpose, we investigated the expression of CYP3A4, CYP2C9 and CYP2B6 in breast cancer tissue using Western Blotting. Ifosfamide turnover was determined by detection of metabolites of the ifosfamide 4-hydroxylation and N-dechloroethylation in tumour microsomal incubations using HPLC/UV and LC/MS. The results demonstrate that all mammary tumours (n=11) reveal CYP3A4 expression; contents varied from 0.5 to 63 pmol mg(protein)(-1). CYP2C9 (n=9) was present in all tested breast tumour samples, too, while CYP2B6 (n=10) protein could not be detected. All measured breast cancer microsomes (n=4) showed an ifosfamide N-dechloroethylation capacity in the range from 0.04 to 0.21 pmol min(-1) mg(protein)(-1), while metabolites of the 4-hydroxylation could not be determined. In conclusion, the detected presence of CYP3A4 and CYP2C9 in breast tumours offers the possibility of intratumoral turnover of ifosfamide. For the first time in the literature, we could demonstrate a turnover of ifosfamide by microsomal preparations from human breast cancer tissue. A calculated modulation of intratumoral ifosfamide turnover could considerably influence its therapeutic efficiency.

The cytokine interleukin (IL)-1 is known to be involved in angiogenesis and metastasis. A prerequisite for IL-1 signalling is the presence of its receptor. Previously we have shown that glioblastoma cells express the IL-1 receptor type I (IL-1RI). In this study we analysed 11 breast tumour specimens for IL-1RI expression using the reverse transcriptase (RT) polymerase chain reaction (PCR). We found all the 11 breast tumours were positive for IL-1RI. This suggests that paracrine or autocrine produced IL-1 mediated signalling via IL-IRI might take place in breast tumours to control the production of pro-tumourigenic factors such as angiogenic factors and support further progression of tumour growth and metastasis.

Cytokines are factors that are known to have both tumor-promoting and inhibitory effects on breast cancer growth depending presumably on their relative concentrations and the presence of other modulating factors. Different cytokines play an important role in controlling the immune system. Interleukin-6 (IL-6) is a pleiotropic cytokine with obviously tumor-promoting and tumor-inhibitory effects. Here, we review the role of IL-6 in in vitro experiments of breast tumor cells, in breast tumor tissues (BTs) and assess its potential as a prognostic indicator in breast cancer patients. A literature search was conducted using PubMed, restricted to articles published in English language. In summary, results regarding the effect of IL-6 on breast tumor cells and on BTs are not unique indicating both tumor-promoting and inhibitory effects of IL-6. Concerning patients' serum IL-6 levels, data are surprisingly unique showing IL-6 to be a negative prognosticator in breast tumor patients.