The steroid hormone aldosterone controls salt balance and hence, blood pressure. It also has been shown to have a significant role in cardiac failure. Although drugs that block the aldosterone receptor are beneficial in the treatment of heart failure, they are limited by potassium retention in the kidney. In order to develop tissue-specific blockers of the aldosterone receptor, it is necessary to identify mechanisms by which the receptor can be activated and/or blocked in these tissues.
Dual Targeting Of The Androgen Receptor For Effective And Durable Control Of Lethal Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$946,177.00
Summary
Preventing binding of androgens to the androgen receptor is the mainstay treatment for advanced prostate cancer, but resistance inevitably develops and the disease becomes lethal. We will develop a new drug that targets a part of the androgen receptor unrelated to its androgen binding function to overcome resistance to current therapy. As this drug will be effective in all stages of prostate cancer, it has high potential to improve survival outcomes for men with prostate cancer.
Identification Of Regulatory Protein Interactions On The CRH Promoter
Funder
National Health and Medical Research Council
Funding Amount
$216,600.00
Summary
CRH made in the brain controls our response to stress, and when made by the placenta it controls when birth will occur. Changes to the stress response can have important implications in heart disease, cancer, obesity and many other diseases. 70% of neonatal death is a result of premature birth, and pre-term babies that survive are more likely to have intellectual handicap or cerebral palsy. This research will help us understand CRH production during stress and pregnancy.
Defining Mechanisms Of Androgen Receptor Action That Impede Breast Cancer Progression
Funder
National Health and Medical Research Council
Funding Amount
$770,619.00
Summary
Androgens (A), commonly considered male hormones, are present in women and may protect them from developing aggressive breast cancer by opposing the cancer-promoting effects of estrogen (E) hormones. We propose that a disturbance in the balance between A and E action in breast cancer worsens the disease and results in a poor outcome for afflicted women. We aim to define how A and E hormones interact in breast cancer, with a view to developing new ways to treat breast cancer and predict outcome.
Role Of Liver Receptor Homologue-1 (LRH-1) In Male Germ Cells
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
Historically the steroid sex hormones - oestrogens and androgens - have been regarded as female- and male- specific sex hormones, respectively. Oestrogens are produced by the ovary and regulate female-specific processes such as ovulation and development of female sexual characteristics, whereas androgens are produced by the testis and regulate male-specific functions. However it is now clear that the distinction between oestrogen and androgen is not a sharp one. For example, we now know that oes ....Historically the steroid sex hormones - oestrogens and androgens - have been regarded as female- and male- specific sex hormones, respectively. Oestrogens are produced by the ovary and regulate female-specific processes such as ovulation and development of female sexual characteristics, whereas androgens are produced by the testis and regulate male-specific functions. However it is now clear that the distinction between oestrogen and androgen is not a sharp one. For example, we now know that oestrogens are produced within the testis and play a very important role in male fertility. Human males patients who are unable to synthesise oestrogens are infertile. Similarly, mice that cannot produce oestrogens are also infertile, due to a defect in sperm production. Oestrogens are therefore critical for normal male fertility, and reduced oestrogen production within the testis may be a significant cause of infertility which would be easily treatable in the clinic. The protein LRH-1 regulates oestrogen production in other tissues. This proposal aims to identify the role of LRH-1 in testicular oestrogen production by identifiying the genes regulated by LRH-1 and the proteins that interact with it in the testis. We also aim to study the structure of these proteins in infertile men. These studies will define new genes associated with male infertility and may lead to the development of more effective treatments for this common condition.Read moreRead less
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
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.
Progesterone Regulation Of Epithelial Cell Lineages In The Breast
Funder
National Health and Medical Research Council
Funding Amount
$534,186.00
Summary
The ovaries play a pivotal role in breast cancer in ways that are unknown. Progesterone increases breast cancer risk, and response to hormonal treatments is critically associated with tumour progesterone receptor content, but how it does this is unknown. We will pursue our findings that progesterone influences cell types in the breast similar to those that become cancerous. This will uncover critical vulnerabilities in breast cancer development and potential targets for prevention and treatment.
The Essential Role Of Androgen Receptor Signalling In Prostate Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$714,375.00
Summary
An urgent objective in prostate cancer clinical practice is to better predict disease course at diagnosis and to identify patients likely to develop metastatic (lethal) disease. We aim to identify clinically-relevant genes - gene pathways that are important in prostate cancer development and progression and which can be used to improve prediction of patient outcome. Prostate cancer management can be improved by tailoring treatments for individual patients.