Role Of SOCS3 In Mammary Gland Development And Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$224,278.00
Summary
We are studying the role of a family of inhibitory molecules (SOCS) in breast tissue; these proteins have been established to have critical roles in the immune system and in regulating growth of the entire animal. We have demonstrated that one member of this family can block the action of the prolactin hormone and have recently obtained evidence that another member of this family, SOCS3, affects survival of breast cells. Furthermore, this protein leads to increased growth when overexpressed in b ....We are studying the role of a family of inhibitory molecules (SOCS) in breast tissue; these proteins have been established to have critical roles in the immune system and in regulating growth of the entire animal. We have demonstrated that one member of this family can block the action of the prolactin hormone and have recently obtained evidence that another member of this family, SOCS3, affects survival of breast cells. Furthermore, this protein leads to increased growth when overexpressed in breast cells. We propose to define the normal role of this gene in mouse mammary tissue and to examine the consequences of expressing the gene at high levels in the mammary glands of mice. Inappropriate expression of this gene may predispose humans to breast cancer. SOCS3 expression will be directly studied in a cohort of primary invasive breast cancers with associated clinical outcome data, to determine whether it has a role as a potential prognostic marker.Read moreRead less
Isolation And Characterisation Of Mouse Mammary Stem And Progenitor Cells
Funder
National Health and Medical Research Council
Funding Amount
$540,202.00
Summary
We have discovered the rare adult stem cell from which all breast epithelial tissue is formed. A single stem cell was found to be capable of giving rise to various cell types in the breast, including the secretory units that produce milk and the ductal cells that transmit milk to the nipple. These cell types are responsible for the majority of human breast tumours. However, the precise 'cell of origin' from which cancers ultimately develop is not known. We recently also found that the stem cell ....We have discovered the rare adult stem cell from which all breast epithelial tissue is formed. A single stem cell was found to be capable of giving rise to various cell types in the breast, including the secretory units that produce milk and the ductal cells that transmit milk to the nipple. These cell types are responsible for the majority of human breast tumours. However, the precise 'cell of origin' from which cancers ultimately develop is not known. We recently also found that the stem cell population is expanded in at least one model of mammary tumours, suggesting that some tumours may arise from the breast stem cell itself. Using mouse models and cellular assays, our aim is to characterise, for the first time, the hierarchy of stem, progenitor ('daughter cells') and mature cells in the mammary gland. These studies will provide insight into the various cell types that give rise to different types of breast cancer. An important evolving concept in cancer biology is that a rare population of cells resident within a tumour, termed 'cancer stem cells', have indefinite growth potential and drive tumour growth. These cells could even account for resistance to conventional anti-cancer treatment, as cells with stem cell-like properties would be able to proliferate extensively and form new tumours. We will apply our knowledge of normal mammary stem cells to determine whether cancer stem cells are indeed present in mouse tumours. Those findings will have direct relevance to human breast cancer. Utlimately, we wish to identify specific cell surface proteins on stem and precursor cells that could provide therapeutic targets. Our studies will provide new insights into the cell types from which breast cancer arise, and how their fate and tumour-forming capacity can be modified by altering gene expression. Delineation of cancer-prone cells and cancer stem cells could reveal new markers and provide new therapeutic strategies to target breast cancer.Read moreRead less
Noncoding RNAs As Prognostic Markers And Therapeutic Targets In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$550,283.00
Summary
Normal human development involves a symphony of genetic changes that control the growth and differentiation of different types of cells during embryogenesis. For many years it has been assumed that most genetic information is transacted by proteins, and that the remaining 98% of the human genome that does not encode proteins was (apart from a limited amount of associated regulatory elements) largely non-functional evolutionary junk. However, this may not be the case. Recent results from our labo ....Normal human development involves a symphony of genetic changes that control the growth and differentiation of different types of cells during embryogenesis. For many years it has been assumed that most genetic information is transacted by proteins, and that the remaining 98% of the human genome that does not encode proteins was (apart from a limited amount of associated regulatory elements) largely non-functional evolutionary junk. However, this may not be the case. Recent results from our laboratory and others have shown that most of our genome and that of other mammals is actually expressed as noncoding RNA, which appears to be developmentally regulated. These RNAs (of which there appear to be tens of thousands, well outnumbering the protein-coding mRNAs) have been referred to as the hidden layer or dark matter of our genome, as they have barely been studied, but appear to play a central role in both normal and abnormal development in humans. There is now increasing evidence that many noncoding RNAs, including small regulatory RNAs called microRNAs, are perturbed in cancer and that these perturbations may be directly involved in, and be an accurate indicator of, cancer state and the direction of cancer progression. If this is true we need to understand the expression and functions of these RNAs in order to develop better diagnostics and perhaps powerful new therapeutics for cancer, based on RNA technology and generic delivery systems. This project will explore the patterns of noncoding RNA expression in normal breast development and in breast cancer, to identify those RNAs that direct or accompany the differentiation of these tissues, and to test the effects of interfering with their expression on these processes. These foundation studies lie at the leading edge of a new understanding of human genetics and cancer, and will provide a platform for future applications in medicine that utilize this information and understanding.Read moreRead less
Biological Role And Partners Of The LIM Domain Protein LMO4 In Breast Epithelium
Funder
National Health and Medical Research Council
Funding Amount
$120,181.00
Summary
Breast cancer is the most common cancer affecting women, with 1 in 14 developing this disease. Although treatment of breast cancer has substantially improved over the last few years, 30% of women diagnosed with this cancer will die from it. One major focus of cancer research is the identification of genes involved in tumour development and definition of their precise role in cancer cells. The design of effective therapeutic inhibitors of cancer requires an understanding of the basic molecular an ....Breast cancer is the most common cancer affecting women, with 1 in 14 developing this disease. Although treatment of breast cancer has substantially improved over the last few years, 30% of women diagnosed with this cancer will die from it. One major focus of cancer research is the identification of genes involved in tumour development and definition of their precise role in cancer cells. The design of effective therapeutic inhibitors of cancer requires an understanding of the basic molecular and cellular biology behind the genetic changes thought to contribute to cancer. The focus of our research is to understand normal cellular mechanisms that drive growth and differentiation of breast tissue, and those changes that lead to breast cancer. Nuclear regulatory proteins have been implicated in many different types of cancers and leukaemias. We aim to identify the key regulators in breast tissue, characterising both their structural properties and biological roles, with the ultimate view of understanding how they divert a normal cell to a cancerous cell.Read moreRead less
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.
Psychosocial Predictors Of Developing Breast Cancer In Women From High Risk Breast Cancer Families
Funder
National Health and Medical Research Council
Funding Amount
$337,018.00
Summary
Systematic review of the literature on psychosocial predictors of developing breast cancer has highlighted the possible roles of life events and distress, possibly mediated by social support and personality. To date there has been little prospective assessment of psychosocial factors in the development of breast cancer. Furthermore, no research in this area has specifically targeted women at increased risk because of their family history, nor explored whether the impact of psychosocial factors s ....Systematic review of the literature on psychosocial predictors of developing breast cancer has highlighted the possible roles of life events and distress, possibly mediated by social support and personality. To date there has been little prospective assessment of psychosocial factors in the development of breast cancer. Furthermore, no research in this area has specifically targeted women at increased risk because of their family history, nor explored whether the impact of psychosocial factors systematically varies according to genetic mutation status. Over the past 5 years it has become possible to isolate two breast cancer genes (BRCA1 and BRCA2). Female carriers of mutations in these susceptibility genes have an estimated lifetime risk of breast cancer of between 37% and 85%. The Kathleen Cuningham Consortium for Research into Familial Breast Cancer (KConFab) was established four years ago to co-ordinate the collection of genetic, epidemiological and clinical data in Australian families with a dominantly inherited predisposition to breast cancer. The systematic recruitment of large numbers of high risk women by KConFab provides a unique and temporary opportunity to address questions concerning psychosocial predictors of disease development in a prospective design with sufficient power, due to the higher rates of breast and ovarian cancer events in this population. We will also be able to explore interactions with genetic mutation status. The study will be a world first, and provide the most rigorous data to date in this area. If this study demonstrates a relationship between psychosocial factors and the development of breast cancer in women from high risk families, subsequent identification of vulnerable individuals and the implementation of appropriate interventions may have a real impact on reducing morbidity and mortality in this population. Furthermore, the results may have implications for all women in reducing breast cancer incidence.Read moreRead less
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.