ErbB2 signaling pathways in the regulation of cathepsin activity
Authors: Rafn, Bo; Szyniatowski, Piotr; Fehrenbacher, Nicole; Bøttzauw, Trine; Nielsen, Christina; Nylandsted, Jesper; Jäättelä, Marja; Kallunki, Tuula
Source: Apmis, Volume 116, Number 5, May 2008 , pp. 439-439(1)
Abstract:Amplification and overexpression of ErbB2 oncogene confers approximately 25–30% of human cancer. It leads to activation of several cellular signaling pathways, increased malignancy and is associated with poor disease outcome. Trastuzumab/herceptin that targets the extracellular domain (ECD) of ErbB2 improves survival from ErbB2 positive breast cancer when given together with chemotherapy, however the treatment is not curative and primary resistance can be expected. Furthermore, the ECD of ErbB2 is frequently shed in primary breast cancer, making it less accessible for the ErbB2 targeted therapies. Thus almost 50% of breast cancer patients overexpressing ErbB2 are initially non responsive to trastuzumab based therapy or eventually become resistant to it.
Increased proteolytic activity is essential for several key tumorigenic processes like angiogenesis, invasion and metastasis. Cathepsin proteases are important players in cancer progression due to their potential to promote these processes and consequently, cathepsin inhibitors have been suggested as anti-cancer drugs. Furthermore, increased activity and expression of cathepsins (cat) B, L and D can reliably be used to predict poor outcome in various cancers including breast cancer.
In order to find alternative ways to control oncogenic ErbB2 signaling, we have explored a cellular model system of breast cancer, where inducible expression of constitutively active ECD truncated ErbB2 in MCF-7 breast cancer cell line results in the induction in the activity of cat B and L and increased malignant phenotype. Human kinome siRNA screen performed in these cells identified few kinases (including ErbB2 itself) each of which was capable for upregulating cat B and L activity in response to ErbB2 expression. Depletion of any of these kinases lead to the downregulation of the cat B and L activity back to the non-induced level as well as to partial reverse of the ErbB2 induced malignant phenotype. Characterization of the kinases and the mechanisms by which they regulate cat B and L activity will be further discussed.
Document Type: Abstract
Publication date: May 1, 2008