Linking Estrogens, Prostatitis And Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$291,309.00
Summary
Prostatitis is very common and a significant health issue that affects men from their 20's. Estrogens promote inflammation and inflammation is associated with the development of cancer. If this study links estrogens, prostatitis and prostate cancer, we can provide better treatment for prostatitis, thus preventing progression to prostate cancer
Molecular Mechanisms Leading To Schizophrenia- The Role Of Estrogen And Estrogen Receptor Alpha
Funder
National Health and Medical Research Council
Funding Amount
$292,639.00
Summary
Schizophrenia (SZ) is a devastating mental illness of unknown cause thought to arise from a derailment of normal brain development where the brain fails to respond to the pubertal surge in sex steroids. This proposal aims to determine the molecular pathogenesis of SZ. The SZ susceptibility gene estrogen receptor alpha and the SZ susceptibility pathway neuregulin-ErbB4 are interrogated. This will lead to the development of novel therapeutics and preventative agents that will halt disease onset.
Characterising The Beneficial Effects Of Estrogen On The Prostate Gland
Funder
National Health and Medical Research Council
Funding Amount
$594,722.00
Summary
Prostate cancer is hormonally regulated and currently managed by androgen ablation. This application seeks to study the potential benefits of estrogen action for the treatment of prostate disease, including PCa. We will show estrogen hormone action causes prostatic cell death, targeting the stem-progenitor cells so the treated prostatic tissue does not regenerate. This project will provide pre-clinical proof of the efficacy of estrogenic compounds as a potential therapy for prostate disease.
Identification And Characterisation Of Cells With High Proliferative Potential In Human Endometrium
Funder
National Health and Medical Research Council
Funding Amount
$409,575.00
Summary
Each month when the uterine lining does not receive an implanting embryo, this lining is shed as part of the menstrual process. It is rapidly replaced with a new functional lining that grows from the basal layer that remains. In post menopausal women, who only have the thin basal layer of the uterine lining, there is rapid regeneration of the lining when they commence hormone replacement therapy. Despite this remarkable regenerative capacity of the uterine lining, nothing is known about the prec ....Each month when the uterine lining does not receive an implanting embryo, this lining is shed as part of the menstrual process. It is rapidly replaced with a new functional lining that grows from the basal layer that remains. In post menopausal women, who only have the thin basal layer of the uterine lining, there is rapid regeneration of the lining when they commence hormone replacement therapy. Despite this remarkable regenerative capacity of the uterine lining, nothing is known about the precursor cells responsible for its cyclical growth. Our preliminary studies have shown that the human uterine lining contains a rare population of cells with high proliferative capacity. This project will identify, characterize and locate these precursor cells in the human uterine lining. It also aims to obtain information on how these precursor cells function in regenerating the uterine lining, how they interact with sex hormones and how their proliferative activity is regulated. Information generated from this project will provide significant new insight into the functioning of the uterine lining. It also has immediate application to common gynaecological diseases associated with abnormal growth of the uterine lining, such as endometriosis, a disease which affects 10% of reproductive age women causing pain and infertility. A better understanding of how these precursor cells may be involved in endometriosis and other gynaecological diseases may ultimately lead to the development of improved medical treatments rather than surgical intervention, which is currently the main form of treatment.Read moreRead less
Role Of Cyclin E2 In Hormone-responsive Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$328,194.00
Summary
The female hormone estrogen stimulates the growth of breast cancers by promoting cell reproduction. We have found that cyclin E2, which is part of the machinery that controls cell reproduction, responds to estrogen. Since abnormally high levels of cyclin E2 are linked with earlier relapse in breast cancer, we wish to understand what role it plays in estrogen action and in breast cancer, how its levels are controlled, and whether too much cyclin E2 interferes with drugs that block estrogen action
Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility t ....Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility that it plays an important role in breast cancer cell proliferation. To better understand how estrogen signals in breast cancer and identify proteins that bind to SRA in cancer cells, we established a collaboration with the O'Malley group at Baylor College of Medicine in Texas (who discovered SRA). We have identified several novel SRA-binding proteins, each of which plays an important role to regulate estrogen and androgen action. Up to this point, we have used a model that has enabled proof of principle studies in the same cancer cells from which SRA was discovered (non-breast or prostate cancer). However, we now need to carefully study the role of these proteins in cancer cells relevant to breast and prostate cancer. Thus, we plan to investigate how these proteins interact with SRA, how they influence nuclear receptor activity and breast and prostate cancer cell proliferation, examine their role in activating other pathways of cell growth in cancer cells, assay the levels of each protein in a series of human breast cancer specimens and solve the physcial 3-D structure of these proteins complexed to the SRA RNA. This work will provide novel insight into several key areas of hormone action in breast and prostate cancer. We hope to identify new markers that can be used for improved diagnosis and for prognosis, and provide structural information for the development of novel therapeutics.Read moreRead less
CHAPERONES IN BREAST CANCER AND ESTROGEN RECEPTOR FUNCTION
Funder
National Health and Medical Research Council
Funding Amount
$256,573.00
Summary
Resistance to hormone therapy in breast cancer is due to adaptations of estrogen signalling mechanisms that result in ERa activation causing growth. So, in the search for new treatments, we are looking for ways to remove ERa from the breast cancer cell. Our study addresses this major issue by focussing on Hsp90 molecular chaperone machinery that is essential for ERa function and in particular immunophilin 'helper' cochaperones that form part of receptor-Hsp90 complexes and fine-tune receptor res ....Resistance to hormone therapy in breast cancer is due to adaptations of estrogen signalling mechanisms that result in ERa activation causing growth. So, in the search for new treatments, we are looking for ways to remove ERa from the breast cancer cell. Our study addresses this major issue by focussing on Hsp90 molecular chaperone machinery that is essential for ERa function and in particular immunophilin 'helper' cochaperones that form part of receptor-Hsp90 complexes and fine-tune receptor responses to hormone. Through a novel mode of action, coumarin-based Hsp90 inhibitors disrupt Hsp90 dimerization causing receptor release and subsequent depletion. We will confirm this novel mechanism for new, high affinity Hsp90 inhibitors and determine which can best interfere with estrogen signalling, either alone or in combination with antiestrogen therapies in the treatment of hormone-dependent cancers. Our study has the potential to pin point the site of action of the immunophilins in ERa to a proline in a region critical for ligand-induced receptoractivation. We will determine the role of the immunophilins and this active-site proline residue in modulating receptor stability and function. Aberrant expression of receptor-associated immunophilins appears linked to endocrine resistance and metastasis in breast cancer. Our study will profile the expression of these chaperones in well defined breast cancer tissue microarrays, and has the potential to identify them as informative biomarkers in the treatment of the disease.Read moreRead less
Why We Have Two Estrogen Receptors: The Role Of ERbeta In Folliculogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$576,053.00
Summary
The female hormone estrogen acts via receptors ERalpha and ERbeta. Little is known about the genes and proteins regulated by ERbeta. Ovarian granulosa cells and granulosa cell tumours express ERbeta. By studying the biology of normal and malignant granulosa cells we hope to understand the role that ERbeta plays in granulosa cells. These studies will identify areas for the development of new therapeutics or treatment strategies for a range of female-specific conditions including ovarian cancer.