Growth Regulation of Hormonal Cancer
Professor Pirkko Härkönen, M.D., Ph.D.
Breast and prostate cancer are the most important types of hormonal cancer, which forms the largest group of malignant diseases. Steroid hormones usually regulate the growth of breast and prostate cancer at their early stage but during tumor progression hormone responsiveness often changes or is gradually lost. Hormone regulation is then replaced by alternative growth mechanisms such as growth factor/growth factor receptor –mediated functions. We have studied the mechanisms and mediators of steroid hormone action in breast and prostate cancer as well as the role of autocrine/ paracrine mechanisms in hormone-sensitive and in hormone resistant tumor growth. We have also looked for possibilities of controlling tumor growth by inhibiting or exploiting these mechanisms. We have previously characterized estrogen and antiestrogen regulation of breast cancer cell growth. We provided early original observations on antiestrogen induction of apoptosis of breast cancer and we have recently resumed studies on the mechanisms of antiestrogeninduced breast cancer cell death. To analyse which estrogen receptors and pathways are used to obtain various cell and tissue specific responses we use transiently and stably transfected cells lines and reporter assays. The data are being used in planning new cell and tissue specific ligands for estrogen receptor to be used as model compounds in drug design.
In studies on the autocrine and paracrine growth mechanisms of hormonal cancer we have demonstrated an important role of prolactin as an autocrine growth factor in prostate recently focused on the fibroblast growth –mediated pathways. We have shown that expression of fibroblast growth factor 8 (FGF-8), which has an important role during embryonal development, is activated in human prostate and ovarian cancer. In experimental models of breast and prostate cancer FGF-8 was found to strongly increase proliferation, migration, invasion, angiogenesis and tumor growth. In order to analyse the role FGF pathways in development of prostate cancer we have produced prostate-targeted FGF-8- transgenic mouse lines. To recognise the target genes involved in these responses microarray analyses of transfected cells and experimental tumors are being used. These studies are also extended to human tumor tissues and metastases. In order to study regulation of invasion, tumor progression and metastasis in breast and prostate cancer we have established assays for in vitro cell migration and invasion as well as models for orthotopical tumors and metastases using intracardiac and pretibial tumor cell implantation. We have also established methods for in vivo tumor imaging including micro x-ray analysis, micro-CT and PET. A special attention will be paid to breast and prostate cancer metastasis to bone. In order to analyse the mechanisms of osteosclerotic and osteolytic bone metastases in breast and prostate cancer, we will exploit co-cultures of tumor cells with bone and bone marrow cells to study the possible interactions and regulation in bone marrow stem cell differentiation. Some methods developed or established in the project are being exploited in drug discovery and development companies. These studies have also led to some published patents and a drug development program and new possibilities for applications are being prepared.
| Senior scientists | Dr. Eeva Valve, Ph.D. |
| Graduate students | Teresa Elo, M.Sc. Anu Kallio, M.Sc. Mirjami Mattila, M.D. Kati Tarkkonen, M.Sc. Sanna Virtanen, M.Sc. Johanna Tuomela, M.Sc. Maija Valta, M.D. |