ELF5 Integrates Prolactin And Progestin Control Of Mammary Gland Development Via Regulation Of Progenitor Cells.
Funder
National Health and Medical Research Council
Funding Amount
$720,515.00
Summary
Elf5 may act as a master-regulator of mammary cell growth during pregnancy. We will demonstrate that Elf5 can replace the requirement for prolactin and progesterone to trigger mammary development and we will determine the stem or progenitor cells Elf5 acts on. Finally we will apply this knowledge to breast cancer cell lines to discover what role Elf5 plays in breast cancer. These experiments have the potential to establish Elf5 as a new therapeutic target for the treatment of breast cancer.
Modulation Of Cytoskeletal Structure By Progesterone Receptor Isoforms
Funder
National Health and Medical Research Council
Funding Amount
$337,650.00
Summary
Ovarian hormones are fundamental regulators of normal cell growth and differentiation, and crucial to the development and progression of breast cancer. We have recently shown that the ovarian hormone progesterone can influence the expression of proteins in the cell scaffolding, known as the cytoskeleton. The cytoskeleton is responsible for maintaining cell shape, and there is growing evidence that alterations in the cytoskeleton can actually cause normal cells to become cancerous. We have shown ....Ovarian hormones are fundamental regulators of normal cell growth and differentiation, and crucial to the development and progression of breast cancer. We have recently shown that the ovarian hormone progesterone can influence the expression of proteins in the cell scaffolding, known as the cytoskeleton. The cytoskeleton is responsible for maintaining cell shape, and there is growing evidence that alterations in the cytoskeleton can actually cause normal cells to become cancerous. We have shown that progesterone affects the levels of a cytoskeletal protein called tropomyosin, which plays a pivotal role in cell shape maintenance. We have hypothesised that this effect may be important in the cell shape changes in breast cancer that lead to metastasis. In this grant, we will investigate the role of the progesterone receptor in controlling the expression of the cytokeleton; we will investigate whether cell shape changes caused by progesterone cause more aggressive behaviour in breast cancer cells and we will determine whether there are changes in cytokeletal proteins in breast tumours. This will provide a rational basis for further studies aimed at delineating the significance of hormonal regulation of cell architecture.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.
Significance And Mechanisms Of Relative Progesterone Receptor Isoform Expression In Normal And Malignant Target Tissues
Funder
National Health and Medical Research Council
Funding Amount
$737,248.00
Summary
The ovarian hormone progesterone has a pivotal role in normal female physiology, in the uterus and ovary; in the mammary gland and in the brain. Human progesterone receptor, through which progesterone exerts its physiological effects, is expressed as two receptor proteins (PRB and PRA). These are identical except that PRA is shorter than PRB and present knowledge supports a role for both proteins in normal physiology. PR is also expressed in breast cancers, where one of its roles may be to inhib ....The ovarian hormone progesterone has a pivotal role in normal female physiology, in the uterus and ovary; in the mammary gland and in the brain. Human progesterone receptor, through which progesterone exerts its physiological effects, is expressed as two receptor proteins (PRB and PRA). These are identical except that PRA is shorter than PRB and present knowledge supports a role for both proteins in normal physiology. PR is also expressed in breast cancers, where one of its roles may be to inhibit oestrogen action and thereby limit tumour growth. A tumour which lacks PR would lack this capacity and this may be clinically associated with poorer prognosis. We have shown that primary tumours lacking PR are more likely to progress to secondary sites and this may provide support for this possibility. In addition, we have shown that over-expression of one PR isoform in breast cancers can be as biologically significant as lack of PR: tumours expressing predominantly one isoform were associated with poorer prognosis features.This project is aimed at investigating how PRA and PRB exert their effects on the range of progesterone targets in normal and malignant tissues. We will do this by determining whether PR isoforms are located in the same nuclear site in cells expressing one versus cells expressing both PR isoforms, to explore whether the proteins act separately in target cells. We will then ask whether the PR activity is different if only one isoform (PRA or PRB) is expressed versus both PRA and PRB. Another major issue which will be explored is the way in which the relative levels of PRA and PRB are controlled, and whether this is altered in breast cancers. Finally, we will explore the clinical significance of PR isoform expression. If achieved, the aims of this project will delineate the individual and combined action of - THIS FIELD WAS OVER 2000 CHARS, TEXT WAS REMOVED TO LODGE THE APPLICATION. A COPY OF THE ORIGINAL APPLICATION IS AVAILABLE FROM ARCHIVE-HARDCOPYRead moreRead less
Glucocorticoid-progesterone Interactions In The Control Of Fetal And Placental Growth
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The growth and function of the placenta is of critical importance to the successful maintenance and completion of human pregnancy. The placenta is effectively the lifeline of the growing fetus through its supply of nutrients, removal of wastes, and coordination of homone signals that regulate fetal growth and development. If the placenta does not perform these functions adequately, the growth rate of the fetus is compromised and can lead to difficulties before and after birth. This project exami ....The growth and function of the placenta is of critical importance to the successful maintenance and completion of human pregnancy. The placenta is effectively the lifeline of the growing fetus through its supply of nutrients, removal of wastes, and coordination of homone signals that regulate fetal growth and development. If the placenta does not perform these functions adequately, the growth rate of the fetus is compromised and can lead to difficulties before and after birth. This project examines how two important steroid hormones, progesterone and glucocorticoids, interact with growth factors in the placenta to control its growth and function. Progesterone is recognized as 'the hormone of pregnancy' as it helps the mother adapt to pregnancy. Progesterone may also affect the placenta by regulating its synthesis and breakdown of other hormones, and the balance between placental cell proliferation and death. These effects of progesterone will be studied in this project. We will also examine how glucocorticoid hormones regulate the growth and function of the placenta. Glucocorticoids are structurally very similar to progesterone, and are secreted by the adrenal gland in increased quantities during pregnancy. Glucocorticoids exert a wide range of effects on the mother, placenta and fetus; indeed, glucocorticoids are recognized clinically as the single-most importnat signal for fetal maturation in late pregnancy. However, too much glucocorticoid retards fetal and placental growth, and in this project we will study how this occurs in the placenta, and how the placenta may protect itself from detrimental effects of glucocorticoids. We will test whether placental growth is restricted by glucocorticoids through their effects on placental growth factor hormones. Overall, these studies could have important implications for the clinical management of pregnancy, particularly in relation to fetal and placental growth.Read moreRead less
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.