Growth factor receptor-mediated signal transduction has been implicated in conferring resistance to conventional chemotherapy on cancer cells. In this study, we delineated a pathway that involves HER2/PI-3K/Akt in mediating multidrug resistance in human breast cancer cells. We found that the cell lines that express both HER2 and HER3 appear to have a higher phosphorylation level of Akt (activated Akt). Transfection of HER2 in MCF7 breast cancer cells that express HER3 caused a phosphoinoside-3 kinase (PI-3K)-dependent activation of Akt, and was associated with an increased resistance of the cells to multiple chemotherapeutic agents (paclitaxel, doxorubicin, 5-fluorouracil, etoposide, and camptothecin). Selective inhibition of PI-3K or Akt activity with their respective dominant-negative expression vectors sensitized the cells to the induction of apoptosis by the chemotherapeutic agents. We further demonstrated that MCF7 cells expressing a constitutively active Akt, in which the phospholipid-interactive PH domain of Akt was replaced by a farnesylation sequence for constitutive membrane anchorage (DPH-Akt1-farn), showed a similar increased resistance to the chemotherapeutic agents. Our results suggest that activation of Akt1 by HER2/PI-3K plays an important role in conferring a broad-spectrum chemoresistance on breast cancer cells and that Akt may therefore be a novel molecular target for therapies that would improve the outcome of patients with breast cancer.

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These results demonstrate a high rate of PLK1-positivity in prostate cancer which suggests involvement of PLK1 in tumorigenesis and progression in this tumor entity. Therefore, targeted strategies focussing on PLK1 inhibition might represent a promising new chemotherapeutic approach in prostate cancer.

The Polo-like kinase (PLK) family comprises three serine/threonine kinases, functionally involved in signal transduction pathways essential for the accomplishment of mitosis in both normal and malignant cells. Moreover, certain PLKs have been functionally linked to cytoskeletal reorganisation. In this study, the expression of PLK1 and PLK3 was determined immunohistochemically in tissue specimen of normal ovaries (n ¼ 9), cystadenomas (n ¼ 17), borderline tumours (n ¼ 13) and ovarian carcinomas (n ¼ 77). PLK 1 and PLK3 expression was low in normal ovarian surface epithelium and borderline tumours, with moderately higher expression levels in cystadenomas. In ovarian carcinomas, 26% of cases were PLK1 positive and 50.6% of cases were PLK3 positive. A positive correlation of both PLK1 and PLK3 expression with indicators of mitotic frequency could be established. The overexpression of either isoenzyme had an impact on patient prognosis with shortened survival time for patients with tumours positive for PLK1 (P ¼ 0.02) and PLK3 (P ¼ 0.02), but only PLK1 expression remained a prognostic factor in multivariate survival analysis (P ¼ 0.03). The results of this study, if interpreted in the context of recently published functional data, suggest that inhibition of PLKs might represent an interesting new targeted approach for chemotherapy of epithelial ovarian cancer. Furthermore, this study suggests that PLK1 is a novel independent prognostic marker in ovarian carcinomas.

Polo-like kinase (PLK) family members are known to be functionally involved in mitotic signaling and in cytoskeletal reorganization in both normal and malignant cells. In this study, expression of PLK1 and PLK3 was determined immunohistochemically in tissue specimens of 135 breast carcinomas, and expression was correlated with clinicopathological parameters and patient prognosis. Strong PLK isoform overexpression was observed in 42.2% (PLK1) and 47.4% (PLK3) of breast carcinomas when compared with non-transformed breast tissue. A positive correlation of PLK isoform expression with tumor grade, vascular invasion, erbB2/HER-2 expression and markers of proliferative activity was evident. Additionally, an inverse correlation of PLK isoform expression and estrogen receptor status was observed. Overexpression of PLK3 but not of PLK1 was significantly linked to reduced median overall (P<0.001) and relapse-free (P=0.021) survival time. PLK3 expression remained an independent prognostic factor for overall (RR=3.2, P=0.002) and relapse-free (RR=2.9, P=0.049) survival in multivariate survival analysis. These results suggest PLK3 as a novel independent prognostic marker in breast cancer and hint toward a role for PLK isoform overexpression in disease progression. Therefore, in vivo inhibition of PLK family members might represent a rewarding approach in the development of new anticancer drugs for this tumor entity.