Steroid hormones, such as oestrogen and cortisol, act in the body by binding 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 remarkably is never made into protein in cells, rather exerting its effects as a RNA. We have identified a novel family of proteins t ....Steroid hormones, such as oestrogen and cortisol, act in the body by binding 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 remarkably is never made into protein in cells, rather exerting its effects as a RNA. We have identified a novel family of proteins that bind to SRA in cancer cells, and may well play a critical role in regulating how SRA modulates genes. This project seeks to understand how this family interacts with SRA, the functional effects on breast cancer cells, and the detailed 3-dimensional structure of the family members coupled with SRA. This work will provide novel insight into how SRA regulates steroid hormone action, and may create new potential avenues for developing therapeutics in breast cancer.Read moreRead less
Progesterone Signalling In Normal And Malignant Breast Relies On Chromosomal Positioning Of Progesterone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$569,346.00
Summary
The cell nucleus carries genetic information that directs cell function. The nucleus is organised into compartments, which are altered in breast cancer, leading to altered function. The ovarian hormone progesterone acts via a receptor, which clumps into foci in the nucleus when active. In cancers, this clumping is disrupted. In this project we will work out how these foci control cell function, and how this leads to the specific functions of progesterone in normal breast and breast cancers.
Cellular Localisation Of Mineralocorticoid Receptor-mediated Vascular Inflammation And Cardiac Fibrosis.
Funder
National Health and Medical Research Council
Funding Amount
$476,264.00
Summary
Cardiovascular disease is a major health and economic burden throughout the world, especially in developed countries and is the leading cause of death and disability in Australia, claiming the lives of over 50,000 Australians each year. Heart failure accounts for many of these deaths and the incidence continues to increase. Two recent large scale clinical trials have shown a 30-35% improvement in patient outcome when a blocker for the mineralocorticoid receptor (MR) is included in current best p ....Cardiovascular disease is a major health and economic burden throughout the world, especially in developed countries and is the leading cause of death and disability in Australia, claiming the lives of over 50,000 Australians each year. Heart failure accounts for many of these deaths and the incidence continues to increase. Two recent large scale clinical trials have shown a 30-35% improvement in patient outcome when a blocker for the mineralocorticoid receptor (MR) is included in current best practice therapy for either heart failure or after a heart attack. The mechanisms underlying these benefits remain to be identified. We have shown that the hormone aldosterone and its receptor, the MR, not only play an important role in the development of high blood pressure but also the progression of cardiac disease. Our most recent studies have shown that blocking the MR not only prevents cardiac fibrosis and vascular damage, but also reverses this process. To understand the mechanisms that translate MR signalling into blood vessel damage and cardiac fibrosis we wish to use mice who have the MR gene inactivated in specific cells only. In this way we can identify those cells critical to the disease process and focus our investigations to these cell types. Understanding the cell specific regulatory mechanisms for the MR may enable the development of heart-specfic blockers of the MR that have minimal, if any side effects.Read moreRead less
The applicant's research is aimed at delineating the molecular mechanisms of action of steroid hormones in the pathogenesis of breast and prostate cancer with the goal of developing new diagnostic, prognostic and therapeutic response parameters of clinica
Impact Of Progesterone Receptor Subnuclear Localisation On Progesterone Action In Endocrine Target Cells
Funder
National Health and Medical Research Council
Funding Amount
$459,514.00
Summary
Breast cancer affects 10,000 Australian women annually and is a major cause of cancer death. The hormone progesterone, which is produced by the ovaries in women, is responsible for some aspects of the development of the normal breast in women and is also implicated in the development and response of breast and endometrial cancers. In normal cells progesterone acts via a specific protein (or receptor) in the nucleus, and we have shown that this protein accumulates into foci when it is active. We ....Breast cancer affects 10,000 Australian women annually and is a major cause of cancer death. The hormone progesterone, which is produced by the ovaries in women, is responsible for some aspects of the development of the normal breast in women and is also implicated in the development and response of breast and endometrial cancers. In normal cells progesterone acts via a specific protein (or receptor) in the nucleus, and we have shown that this protein accumulates into foci when it is active. We have noticed that in cancers, this accumulation is disrupted, and this is a bad sign for the cancer. As breast cancer develops, it causes many dramatic changes in the structure of cells of the breast, and particularly in the nucleus, which carries the genetic information that programs cancer cell behaviour. The nucleus normally is highly organised into compartments, which carry out different functions of the cell, such as duplication of the DNA, repair of DNA after damage, and switching on and off of particular genes important to the function of the cell. This organisation is altered dramatically in cancer cells, and it seems that this altered organisation is responsible for altered function. In this project we aim to work out what makes the receptor for progesterone form foci, how these foci are involved in the action of progesterone, and how the changed structure of the nucleus changes this process. This project will link the structure of the cell nucleus with the ability of progesterone to switch on or off particular genes, and this will provide the first signposts of how changes seen in cancer cell nuclei are reflected in changed hormonal signalling. Healthy women are regularly exposed to progestins in oral contraceptives and hormone replacement therapy. The known increased risk of breast cancer as a result of exposure to progestins creates an imperative to understand how progesterone may have aberrant effects. This project will address this important health issue.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
Much of our current knowledge on development of external genitalia (ExG), the penis and clitoris, comes from 20 &70 year-old studies (1); but with significant developments in contemporary imaging and new mouse models, we have new data. The overall goal of this project is to prove the hypothesis that penile and clitoral development is estrogen- (and androgen-) dependent and, to show that the administration of exogenous endocrine disrupting chemicals that alter the balance between estrogen and and ....Much of our current knowledge on development of external genitalia (ExG), the penis and clitoris, comes from 20 &70 year-old studies (1); but with significant developments in contemporary imaging and new mouse models, we have new data. The overall goal of this project is to prove the hypothesis that penile and clitoral development is estrogen- (and androgen-) dependent and, to show that the administration of exogenous endocrine disrupting chemicals that alter the balance between estrogen and androgen will disrupt ExG development.Read moreRead less