Progesterone Receptor Action In The Normal Human Breast
Funder
National Health and Medical Research Council
Funding Amount
$360,500.00
Summary
Breast cancer affects 10000 Australian women annually and is a major cause of cancer-related death. The hormone progesterone, which is produced by the ovaries in women, is responsible for many aspects of normal breast development and function. Progesterone is also a major component of hormone replacement therapy (HRT) and oral contraceptives (OCP), which are taken by millions of women worldwide. It has been established that the use of HRT and OCP containing progesterone-like hormones leads to in ....Breast cancer affects 10000 Australian women annually and is a major cause of cancer-related death. The hormone progesterone, which is produced by the ovaries in women, is responsible for many aspects of normal breast development and function. Progesterone is also a major component of hormone replacement therapy (HRT) and oral contraceptives (OCP), which are taken by millions of women worldwide. It has been established that the use of HRT and OCP containing progesterone-like hormones leads to increased breast cancer risk, yet the ways in which this happens are not known. Breast cancer is thought to begin early in a woman's life, with a number of genetic changes that accumulate over a period of many years; the majority of breast malignancies are not diagnosed until after the age of 50. However, there are recent indications that some areas of apparently normal breast have undergone a few genetic changes, even in women with no evidence of malignancy, but there is nothing known about how progesterone may affect these areas and possibly encourage breast cancer development. This project will firstly explore the influence of progesterone on the normal breast, to clarify how this hormone acts in normal cells. We will then investigate the involvement of progesterone in areas of normal breast that have undergone genetic alterations. This will determine whether one way in which progesterone may increase breast cancer risk is by affecting the behaviour of cells with genetic changes to make them more likely to develop further changes and subsequently progress to full cancer development. If women are to continue to derive the benefits of progesterone exposure, there is a compelling need to appreciate how progesterone acts in the normal breast and how it increases breast cancer risk. Achievement of the aims of this project will provide invaluable knowledge and greatly increase our understanding in this area.Read moreRead less
The Nuclear Growth Hormone Receptor- Its Actions And Mechanism Of Nuclear Translocation
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourog ....We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourogenesis, and to define the physiological roles of nuclear GH receptor, we will define the transport process which carries the receptor to the nucleus and block it. We will also seek to define how the receptor in the nucleus interacts directly with DNA to inhibit programmed cell death. To carry out these projects we will use sophisticated proteomics -mass spectrometry to identify the proteins interacting with the receptor in the transport and gene activation processes. The role of candidates will be tested by preventing their expression or by direct inhibition of their action using drugs or dominant negative versions. These approaches will provide leads to new anti-cancer therapeutics, and therapies for blocking diabetic blindness and kidney failure.Read moreRead less
Constitutive Activation Of The Growth Hormone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$566,277.00
Summary
Growth hormone regulates growth, metabolism, bone, stem cells and longevity, and cancer. These actions are mediated by the GH receptor, and here we seek to understand how it is activated by the hormone through receptor constructs which are active without hormone, to different degrees. We will use these to elucidate its signaling properties, its ability to promote cancer, to grow muscle, and whether cases of giantism and cancer are a consequence of the activating mutations we have identified.
REGULATION OF ANDROGEN RECEPTOR And ErbB-2 GENE EXPRESSION IN PROSTATE CANCER: ROLE OF THE HU PROTEINS
Funder
National Health and Medical Research Council
Funding Amount
$471,000.00
Summary
Carcinoma of the prostate (PCa) is the most common malignancy affecting males and causes enormous morbidity and mortality in Australia. It is the second leading cause of death in men in Western countries. About one third of men relapse after radical prostatectomy because of previously undetectable metastatic disease. Androgens, acting via the androgen receptor (AR) a nuclear transcription factor that regulates a set of largely unknown androgen-responsive genes, promote the growth of prostate can ....Carcinoma of the prostate (PCa) is the most common malignancy affecting males and causes enormous morbidity and mortality in Australia. It is the second leading cause of death in men in Western countries. About one third of men relapse after radical prostatectomy because of previously undetectable metastatic disease. Androgens, acting via the androgen receptor (AR) a nuclear transcription factor that regulates a set of largely unknown androgen-responsive genes, promote the growth of prostate cancer cells. Thus the AR is a major target for therapy. Even when the disease is unresponsive to androgen withdrawal, the AR is present. Furthermore, we know that these PCa cells recruit other androgen-independent pathways to activate growth. One such pathway is the erbB-2 signaling cascade, which drives the cells towards proliferation. Proteins that bind to RNA, the cellular messenger, are playing an increasing role in the biology of cancer. HuR, a member of the Hu-Elav family, augments growth of colon cancer cells, and is associted with poor outcomes in ovarian and brain malignancies. We have recently identified the first proteins that bind to AR and erbB-2 mRNA. Remarkably, HuR binds to both sequences. Furthermore, HuD, another member of the Hu-Elav family which is normally only found in the brain, is aberrantly expressed in human PCa. In this Project we will determine the effects of these proteins on the growth of human PCa cells in culture and in whole animal models. We will also evaluate their presence in a large array of human PCa specimens. It is envisaged that this work will develop novel links between the two pathways bringing them together in a previously unrecognised manner. We also aim to solve the molecular structure of Hu proteins bound to the AR mRNA. Outcomes of the work will include new potential tests for prostate cancer and improved prognosis prediction, and establishment of a foundation for the development of novel targets for therapy.Read moreRead less
Diabetic cardiomyopathy (DiabCM) is common in people with diabetes. It predisposes to heat failure. Its cause remains unclear and there is no specific treatment for DiabCM. Inflammation is a fundamental tissue response to a metabolic insult and it occur in DiabCM. The central hypothesis in this work is that inflammation through myocardial macrophage cells contributes to DiabCM. This hypothesis will be tested in animal models and also in cell culutre studies.