A Link Between Breast Cancer and Estrogen
03/03/10 11:40 Filed in: GenomeWeb Daily Scan
Submitted by S. Pelech - Kinexus on Wed, 03/03/2010 - 16:31.
While a link between breast cancer and estrogen is well established, I am less convinced that the mixed-lineage kinase 3 (MLK3) generally acts to inhibit breast tumour development. MLK3 is a ubiquitous protein kinase in diverse human tissues and highly conserved in the animals and plants. MLK3 is implicated as a kinase that phosphorylates and activates the MKK4 and MKK7 protein kinases, which in turn phosphorylate and activate the JNK protein kinases, which in turn phosphorylate and activate the c-Jun transcription factor. At Kinexus Bioinformatics Corporate, we have studied this and other signal transduction pathways in hundreds of cell lines and tissue samples. In many human cancer cell lines, we have found that contrary to its pro-apoptotic role in many non-immune cell-types, MKK4, MKK7 and JNK can actually act in an anti-apoptotic manner to enhance tumour cell survivability. In a detailed examination of 40 different human breast tumour cell lines for the phosphorylation of 80 key regulatory phosphorylation sites, we observed that every mammary cell line displayed markedly different patterns of protein phosphorylation. It may well be that every cancer is unique in its cell signalling architecture. Estrogen-treatment of cells induces profound changes in the levels of expressions of many different protein kinases in addition to MLK3. Relatively little general kinase-specificity data on the MLK3 inhibitor drug CEP-11004 that was used by Rangasamy et al. in the Loyola University study appears to be available, so caution should be exercised in the interpretation of their findings with this drug. Finally, even if it was confirmed that MLK3 acts to reduce cancer cell survival in some patients with breast tumours, it is unlikely to be a good drug target as it is very difficult to find a compound that directly enhances the activity of a missing or phosphorylation repressed enzyme. With few exceptions (e.g. tumour promoters that activate protein kinase C isoforms), most known kinase drugs are inhibitors.
Link to the original blog post
While a link between breast cancer and estrogen is well established, I am less convinced that the mixed-lineage kinase 3 (MLK3) generally acts to inhibit breast tumour development. MLK3 is a ubiquitous protein kinase in diverse human tissues and highly conserved in the animals and plants. MLK3 is implicated as a kinase that phosphorylates and activates the MKK4 and MKK7 protein kinases, which in turn phosphorylate and activate the JNK protein kinases, which in turn phosphorylate and activate the c-Jun transcription factor. At Kinexus Bioinformatics Corporate, we have studied this and other signal transduction pathways in hundreds of cell lines and tissue samples. In many human cancer cell lines, we have found that contrary to its pro-apoptotic role in many non-immune cell-types, MKK4, MKK7 and JNK can actually act in an anti-apoptotic manner to enhance tumour cell survivability. In a detailed examination of 40 different human breast tumour cell lines for the phosphorylation of 80 key regulatory phosphorylation sites, we observed that every mammary cell line displayed markedly different patterns of protein phosphorylation. It may well be that every cancer is unique in its cell signalling architecture. Estrogen-treatment of cells induces profound changes in the levels of expressions of many different protein kinases in addition to MLK3. Relatively little general kinase-specificity data on the MLK3 inhibitor drug CEP-11004 that was used by Rangasamy et al. in the Loyola University study appears to be available, so caution should be exercised in the interpretation of their findings with this drug. Finally, even if it was confirmed that MLK3 acts to reduce cancer cell survival in some patients with breast tumours, it is unlikely to be a good drug target as it is very difficult to find a compound that directly enhances the activity of a missing or phosphorylation repressed enzyme. With few exceptions (e.g. tumour promoters that activate protein kinase C isoforms), most known kinase drugs are inhibitors.
Link to the original blog post