ESR – estrogen signaling research group - Karin Dahlman-Wright
The overall goal is the development of novel therapeutic strategies targeting estrogen signaling in metabolic disease, particularly type 2 diabetes (T2D) and breast cancer. There is substantial evidence for the involvement of estrogen signaling and estrogen receptors (ERs) in T2D combined with a great unmet medical need for this disease. Estrogen signaling promotes breast cancer growth and ER antagonists represent first line therapy for ER positive breast cancer. However, all tumors do not respond to this therapy and additionally many tumors eventually acquire ER antagonist resistance supporting a need to develop novel therapeutic strategies.
ERα knock-out (KO) mice are obese and display insulin resistance; however, the target tissues responsible for these effects remain elusive. Tissue-selective KO animals are well posed to address this issue and we have generated mice with ERα KO in hepatocytes, adipocytes and pancreatic β-cells. These studies revealed that hepatocyte-selective ERα ablation does not recapitulate the T2D phenotype. We are exploring several avenues to modulate estrogen signaling in breast cancer cells.
We have demonstrated that members of a family of E3 ubiquitin ligases can modulate ERα levels and cell proliferation and suggest that these proteins could constitute novel drug targets. The extensive cross talk between estrogen signaling and AP-1 signaling that we have described indicates a potential of modulators of AP-1 family in management of breast cancer.
The group is approaching the molecular mechanism of estrogen signaling in metabolic disease and breast cancer combining phenotypic and functional genomics data with the ultimate goal to identify novel diagnostic criteria and drug targets.