Progesterone Regulation Of Epithelial Expansion In The Normal Human Breast
Funder
National Health and Medical Research Council
Funding Amount
$556,393.00
Summary
The ovaries play a pivotal role in breast cancer. Progesterone increases breast cancer risk, and this is likely to be a subversion of its role in the normal breast, which is to participate in the normal expansion of the epithelial cells during the menstrual cycle, but how it does this is unknown. We will explore how progesterone influences cell types in the breast similar to those that become cancerous. This will uncover potential targets for prevention and treatment.
Novel Interactions Between GnRH Receptor And E2F4 Transcription Factor.
Funder
National Health and Medical Research Council
Funding Amount
$462,750.00
Summary
The reproductive endocrine system is under the control of gonadotropin-releasing hormone (GnRH), signalling via its G-protein coupled receptor (GPCR) in the anterior pituitary gland. The GnRH receptor (GnRHR) is the drug target for the treatment of a range of endocrine-related disorders as well as hormone-dependent cancers. Sustained treatment with either GnRH agonists or antagonists can block gonadotropin secretion indirectly, via down-regulation of the pituitary receptor resulting in a reducti ....The reproductive endocrine system is under the control of gonadotropin-releasing hormone (GnRH), signalling via its G-protein coupled receptor (GPCR) in the anterior pituitary gland. The GnRH receptor (GnRHR) is the drug target for the treatment of a range of endocrine-related disorders as well as hormone-dependent cancers. Sustained treatment with either GnRH agonists or antagonists can block gonadotropin secretion indirectly, via down-regulation of the pituitary receptor resulting in a reduction of gonadotropin secretion and consequent decline in steroid production. As the majority of tumours treated with GnRH analogues are hormone-dependent, this starves the tumour of the steroid support required for growth. However, the concept of a direct anti-tumour effect of GnRH, independent of the pituitary-gonadal axis, is supported by the in vitro inhibition of both cell growth and DNA synthesis in a number of tumour cell lines. Despite the wide use of GnRH analogues, the molecular basis of the growth inhibitory effects resulting from the activation of this receptor is not fully understood. Unravelling the protein interactions underlying receptor-mediated signalling events will provide valuable information towards understanding of receptor function in vivo. We have identified a novel interaction involving the GnRHR and E2F4, a transcription factor involved in suppression of the transcription of genes involved in cell cycle progression. In addition, over 80% of E2F4 knockout mice are sterile. Owing to the role of the GnRHR in the reproductive pathway we are interested in determining whether the GnRHR-E2F4 interaction has an influence on the development of the hypothalamic-pituitary-gonadal axis, hence affecting reproductive capacity. The interaction identified and studied in this proposal has implications for the treatment of reproductive tumours, such as those of the breast and prostate, and understanding the development of the hypothalamic-pituitary-gonadal axis.Read moreRead less
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
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
Aromatase Regulation By P53 And HIF-1alpha In Obesity And Post-menopausal Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$607,523.00
Summary
Current hormone therapy for breast cancer using inhibitors of oestrogen production results in serious side-effects including bone loss, joint pain and possibly cognitive issues. Our current work is aimed at understanding how oestrogen production is regulated with the goal of developing breast-specific inhibitors of oestrogen production to obviate these problems. In addition, this work is aimed at devising therapeutic intervention to break the linkage between obesity and breast cancer.