Professor Jan-Erik Damber
Professor Göran Landberg
Prostate cancer (PC) is the most common malignant disease and the leading cause of cancer-related death in Sweden. In most cases, PC is initially androgen-dependent and responds well to androgen deprivation therapy. Unfortunately, within 2 years, most tumors become androgen resistant and metastasize. To find new therapeutic pathways, the largely unknown molecular and cellular mechanisms this progression must be elucidated. One mechanism by which PC cells might survive in an androgen-depleted environment is upregulation of the AR. Progression to androgen resistance is also associated with increased angiogenesis. In experimental and human PCs, Dr. Damber and others have shown that androgens may regulate the tumor vasculature before the tumor becomes androgen resistant. Thus, lack of control of PC endothelial cells by androgens might accompany the transition to androgen resistance. Highly malignant and metastatic PC is characterized by increased angiogenesis and an inability to respond to androgen ablative therapy with tumor cell apoptosis. The aim of this module is to improve treatment of advanced PC by investigating the mechanisms of action for androgen ablative therapy, focusing on development of androgen resistance.
The researchers will analyze AR signaling, angiogenesis, invasiveness, and metastatic ability in a model of androgen-resistant PC and in hormone-sensitive tumors. Paracrine communication between PC cells and endothelial cells is of paramount importance for understanding why anti-angiogenesis therapies often fail. How PC endothelial cells become resistant to androgens will be studied by co-culture of endothelial and PC cells in different stages of malignancy. Patients with PC who develop androgen resistance are followed and PC biopsies are taken at regular intervals. These clinical studies will enable the researchers to confirm the experimental findings. Data from the Swedish National Registry of PC show that the age-standardized use of endocrine therapy is gradually increasing. The impact of this change on mortality and morbidity (e.g., osteoporosis, sexual and mental disorders, and cardiovascular health) will be studied using an epidemiological approach. The importance of hereditary factors for development of PC will also be studied.
PC is becoming a significant health problem in the Western world, and advanced-stage tumors are currently incurable. Combining basic experimental research with clinical studies offers the greatest hope of developing new therapeutic strategies to fight this important disease.
CEROSS research in Göteborg is disease focused and covers the major SS-related disorders except breast cancer. Therefore, a close collaboration has been established with the breast cancer research group of Göran Landberg (Malmö, Sweden) to explore the mechanism of action for estrogens in the development and treatment of breast cancer. New additive schedules that improve endocrine treatment for breast cancer by targeting key proteins in the cell cycle and pathways affecting ERs will be explored and developed. Analyses of patient materials and experimental systems are key tools for successfully defining new targets for combined endocrine treatment in breast cancer. In the search for common regulatory events of proliferation and invasion in tumors, Dr. Landberg and colleagues have shown that actively invading cells often exhibit low-level proliferation that is governed by the cdk-inhibitor p16. Thus, invasion is not necessarily analogous with proliferation. This finding implies a paradigm shift in the understanding of two central processes in malignant behavior.
SS ablative therapy is of utmost importance in the treatment of prostate and breast cancers. Such treatment induces tumor cell apoptosis and resistance to the apoptotic program is one mechanism by which tumors become refractory to therapy. Thus, a major goal of this project is to understand the precise relationship between SS and apoptosis in the regulation of apoptosis in cancer and in normal tissue.
Under physiological condition, female reproduction depends on the coordinated function of the ovary, Fallopian tube, uterus, hypothalamus, and pituitary. This coordination is at least partly mediated by the SS progesterone. Progesterone is believed to exert its biological actions largely through interactions with the transcription-regulating nuclear progesterone receptor (nPR), a member of the steroid/nuclear receptors super family. A group of newly discovered membrane receptors for progesterone (mPRs), expressed in reproductive tissue and the brain, are potentially part of this interplay. Most oocyte-containing follicles are removed by apoptosis, and ovarian-produced progesterone is an important regulator of this process. Dr. Billig’s aims are to explore the expression and regulation of nPRs and mPRs and their isoforms and to investigate the mechanism underlying nPR regulation of cell survival and apoptosis. For these studies, he will analyze microarray data and posttranslational protein modifications (e.g., isoprenylation and sumoylation).