Stress activated signaling pathways in cancer development
Deregulated cell signaling pathways play prominent roles in cancer. They can be the main force driving cancer development, and they can enhance proliferation and metastasis and cause resistance to therapy. Some signaling pathways are activated by stress signals and are particularly relevant for cancer patients because treatment with chemotherapeutic agents and glucocorticoids as well as potentially high levels of stress hormones will activate these. We study the molecular mechanisms associated with cancer development in these pathways and aim to identify novel targets for cancer therapy.
SRC-3
Steroid receptor co-activator 3 (SRC-3), also known as amplified in breast cancer 1 (AIB-1), is associated with cancer development in several tissues. It is a transcriptional co-activator which can regulate transcription through interaction with steroid receptors (ER, PR and AR), but also with other transcription factors like AP-1, NF-κB and HIF-1α. Post translational modifications regulate the activity of SRC-3, and especially the phosphorylation of S857 have been shown to be important for proliferation and migration of cancer cells. We have chosen lung and breast cancer as model systems to study the function of this co-activator in cancer development. For this we have generated SRC-3 KO cell lines by use of the CRISPR-Cas gene editing system and have used lentiviral transduction to re-introduce (rescue) either wild type SRC-3 or S857A mutant SRC-3. To study the function of the S857 phosphorylation we have successfully generated a phosphospesific antibody against p-S857 and have by use of this antibody in combination with the gene edited cell lines identified MK2 as the kinase responsible for the phosphorylation of SRC-3 S857. MK2 is a downstream kinase in the stress activated p38MAPK signaling pathway. We are now in the process of identifying genes whose regulation is affected by this phosphorylation and the activity of the P38-MK2-SRC-3 pathway.
GR
Glucocorticoids (GCs) are natural stress-hormones important for homeostasis and they regulate several processes, among them immune responses and metabolism. Because of their immune-suppressive and anti-inflammatory properties synthetic glucocorticoids are much used in the clinic. For cancer treatment they are often used to alleviate side effects such as nausea, edema and low appetite. GCs activate the glucocorticoid receptor (GR) which works as a transcription factor. The GR is ubiquitously expressed, and for some cancers the GR expression level in the tumor tissue is associated with tumor development, response to treatment and patient prognosis. We are studying the interaction between the p38 MAPK signaling pathway and GR and is particularly interested in one point of interaction that is associated with cancer development that seems to be differentially regulated in the triple negative and ER positive subtypes of breast cancer.