Cohesin Dysfunction: Potential New Route To Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$386,511.00
Summary
This proposal aims to investigate the role of a newly-discovered chromosomal and DNA repair protein, Rad21, in breast cancer. Rad21 is a gene, present in many species and essential for accurate chromosome separation. Based on its' known function in different species, it is conceivable that its' dysfunction could fuel cancer progression by promoting genetic instability, eg. gains or losses of chromosomes, commonly associated with human cancers. No definitive data currently exists as regards the p ....This proposal aims to investigate the role of a newly-discovered chromosomal and DNA repair protein, Rad21, in breast cancer. Rad21 is a gene, present in many species and essential for accurate chromosome separation. Based on its' known function in different species, it is conceivable that its' dysfunction could fuel cancer progression by promoting genetic instability, eg. gains or losses of chromosomes, commonly associated with human cancers. No definitive data currently exists as regards the potential role of this gene in cancer development. This study is thus the first systematic investigation towards understanding the function of this potential cancer-causing gene. Although the proposed study focuses on breast cancers, it could, in principle, apply to other cancer types in which its' overactivity has recently be oberserved. This study could also have implications for the response of humans to radio- and chemo-therapy for cancer treatmentRead moreRead less
Genome-wide SNP Analysis Of Fibroblasts Juxtaposed Or Distant From Epithelial Breast And Ovarian Tumours
Funder
National Health and Medical Research Council
Funding Amount
$401,763.00
Summary
In the past it was believed that the driving factor in the process of cancer devlopment was the cancer tissue itself. More recently however, it has become clear that the process is far more complex and that many aspects of human biology can profoundly influence both an individuals presiposition to cancer and the severity of disease. Many laboratories, including our own, have shown that gene mutations frequently occur in cancer tissue but recent studies have suggested that the apparently normal t ....In the past it was believed that the driving factor in the process of cancer devlopment was the cancer tissue itself. More recently however, it has become clear that the process is far more complex and that many aspects of human biology can profoundly influence both an individuals presiposition to cancer and the severity of disease. Many laboratories, including our own, have shown that gene mutations frequently occur in cancer tissue but recent studies have suggested that the apparently normal tissue surrounding the cancer (often referred to stroma) may also contain mutations. This so called 'cancer associated stroma'(CAS) is also thought to harbour genetic mutations and some studies have shown that without these mutations the cancer cannot survive. At present we have only had glimpses of the genetic alterations that may occur in CAS and there is an urgent need to fully understand the interplay between CAS and frankly cancerous tissue. Our laboratory will utilise high density, genome-wide screening technologies to search for novel mutations in CAS from breast and ovarian cancers. A complete understanding of the role stroma plays in cancer development is likely to lead to novel ways of treating and preventing cancer. Consequently, the identification of the full repertoire of stroma-derived cancer promoting genes is emerging as one of the most important areas in cancer research. The identification of these genes could lead to the development of novel diagnostic markers for use in cancer detection, diagnosis and-or prognosis.Read moreRead less
Genome-wide Study Of Loss Of Heterozygosity Using High Density SNP Arrays To Identify Breast Cancer Predisposition Genes
Funder
National Health and Medical Research Council
Funding Amount
$542,599.00
Summary
The genes responsible for the majority of breast cancer families remain unknown. The genes BRCA1 and BRCA2 can prevent the development of cancer and represent a class of gene known collectively as 'tumor suppressors'. One of the hallmarks of these genes is that they show loss of the normal copy of the gene in tumors that arise in individual carrying one inherited, mutated copy. The broad aim of this proposal is to exploit this phenomenon to identify novel tumor suppressor genes that predispose t ....The genes responsible for the majority of breast cancer families remain unknown. The genes BRCA1 and BRCA2 can prevent the development of cancer and represent a class of gene known collectively as 'tumor suppressors'. One of the hallmarks of these genes is that they show loss of the normal copy of the gene in tumors that arise in individual carrying one inherited, mutated copy. The broad aim of this proposal is to exploit this phenomenon to identify novel tumor suppressor genes that predispose to familial breast cancer. This will be done by analyzing tumors from families that do not have either BRCA1 or BRCA2 mutations. Candidate tumor suppressor genes will be identified when tumors from different individuals in the same family all appear to have lost one copy of a gene, and retained the same copy, in a particular chromosomal region. We study tumours from non-BRCA1-2 breast cancer families using genetic techniques that are able to rapidly and accurately identify which parts of the chromosomes have been lost. Families will be identified in which all the tumors have lost exactly the same part of the chromosome. Next, we will exploit the fact that the entire sequence of the human genome is completed to find out which genes are located within the candidate region. We will then apply other technologies to identify which of these 'candidate genes' is actually responsible for the cancer in that family. Following this, we will investigate other families with a history of breast cancer to see how many can be accounted for by mutations in this gene. It is possible that we may identify more than on breast cancer gene using this powerful approach. Identification of new breast cancer predisposition genes would have major clinical relevance to the families directly affected, and much wider relevance if the same gene (or pathway) is later found to be involved in the causes of other familial or sporadic breast cancers.Read moreRead less
Biological And Clinical Characterisation Of Human Phosphatidylinositide 3-kinase Mutations
Funder
National Health and Medical Research Council
Funding Amount
$553,776.00
Summary
Colorectal and breast cancers are the two most common registrable cancers in Australia and are second only to lung cancer in the total number of cancer deaths each year (4,678 and 2,612 deaths in 1997 for colorectal and breast, respectively). Ovarian cancer kills a further 740 women each year (Source: Cancer in Australia 1997, AIHW and AACR 2000). Thus, on average, one Australian dies of colorectal, breast or ovarian cancer every hour! Clearly, these are major diseases with a significant impact ....Colorectal and breast cancers are the two most common registrable cancers in Australia and are second only to lung cancer in the total number of cancer deaths each year (4,678 and 2,612 deaths in 1997 for colorectal and breast, respectively). Ovarian cancer kills a further 740 women each year (Source: Cancer in Australia 1997, AIHW and AACR 2000). Thus, on average, one Australian dies of colorectal, breast or ovarian cancer every hour! Clearly, these are major diseases with a significant impact on our society. Unfortunately, though, we still do not understand the basic molecular and-or biochemical abnormalities that initiate and-or drive the development of these cancers. Our laboratory has recently reported a high frequency of mutation of the phosphoinositide 3-kinase (PI3K) gene PIK3CA in breast, colorectal and ovarian tumours. This work, funded by the NHMRC, has not only confirmed that PI3K is a bone fide human oncogene but also that mutations in the PI3K family of genes are one of the most common, and thus potentially one of the most important, genetic abnormalities in solid human tumours. In the current proposal, we aim to extend and complement our genetic studies by addressing the biological consequences and clinical significance of the mutations we have identified. This will provide crucial new insights into the biology of human tumourigenesis and further our understanding of the critical pathways and processes involved in the initiation and progression of human tumours. Such knowledge will help us to identify novel markers for diagnosis, prognosis and the early detection of cancer and enable a rational approach to the design of new anti-cancer therapies.Read moreRead less
Tailored Treatments For Premenopausal Patients With Endocrine Responsive Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$257,250.00
Summary
For women under 50 years with hormone receptor positive (ER+) breast cancer, adjuvant treatment with chemotherapy, tamoxifen and ovarian ablation are each effective and reduce recurrence. Combining two treatments is more effective than one, although it is uncertain if combining three provides extra benefit. Ovarian ablation by surgery or radiation is permanent, but reversible ovarian suppression by injections is now available. Three international trials called SOFT, TEXT and PERCHE have been des ....For women under 50 years with hormone receptor positive (ER+) breast cancer, adjuvant treatment with chemotherapy, tamoxifen and ovarian ablation are each effective and reduce recurrence. Combining two treatments is more effective than one, although it is uncertain if combining three provides extra benefit. Ovarian ablation by surgery or radiation is permanent, but reversible ovarian suppression by injections is now available. Three international trials called SOFT, TEXT and PERCHE have been designed for adjuvant therapy of premenopausal women with ER+ breast cancer. These trials take into account regional-country variations in medical practice and different patient choices in this setting. SOFT is for very young women and tests the benefit of adding ovarian suppression in a woman who has received chemotherapy, with tamoxifen planned, but who has not gone into menopause after chemotherapy. The trial also tests if substituting a newer drug called exemestane for tamoxifen, combined with ovarian function suppression is more effective. TEXT is for women who would ordinarily be treated with ovarian suppression plus tamoxifen. The TEXT trial also tests substitution of exemestane for tamoxifen. Exemestane is an aromatase inhibitor. Aromatase inhibitors lower oestrogen levels, but only work if the ovaries are inactive. Recent trials in post menopausal women show aromatase inhibitors are more effective than tamoxifen, and we aim to replicate that improvement in younger women by combining exemestane with ovarian suppression. PERCHE is for women in whom the benefit of chemotherapy is uncertain, for example those with limited or no spread to lymph nodes. All women receive combined endocrine treatment with ovarian suppression plus tamoxifen, and are randomised to receive in addition, either chemotherapy or no chemotherapy, to see if results differ.Read moreRead less
Follow-up Of Women On A Randomised Clinical Trial Of Adjuvant Docetaxel And Doxorubicin For Node Positive Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$113,250.00
Summary
This project is testing the use of a drug docetaxel in the post-operative (adjuvant) treatment of women with breast cancer and involved lymph nodes (N+). Until recently the drug doxorubicin was the most active chemotherapy drug for breast cancer, but more recently a new group of chemotherapy drugs called taxanes were identified. One taxane called docetaxel may be even more effective than doxoubicin. Using available treatments that include doxorubicin based chemotherapy, approximately half the wo ....This project is testing the use of a drug docetaxel in the post-operative (adjuvant) treatment of women with breast cancer and involved lymph nodes (N+). Until recently the drug doxorubicin was the most active chemotherapy drug for breast cancer, but more recently a new group of chemotherapy drugs called taxanes were identified. One taxane called docetaxel may be even more effective than doxoubicin. Using available treatments that include doxorubicin based chemotherapy, approximately half the women with N+ breast cancer experience recurrence of their cancer. It is therefore important to test whether the inclusion of docetaxel in adjuvant therapy can reduce relapses. If docetaxel is to be included, it is also important to test whether it is best to combine it with doxorubicin at the same time (which for safety reasons requires the doses of each drug to be reduced), versus giving them sequentially at full dose. Currently, docetaxel is not approved nor funded for use in early breast cancer in Australia. There are several international trials testing the inclusion of taxanes in the adjuvant therapy of breast cancer. However this trial stands out, because all the women in the trial receive chemotherapy of at least 6 months. In some other trials, testing the possible benefit of adding a taxane, women in the control treatment group (who were randomised not to receive the taxane) received only 3 months of treatment, which makes it difficult to distinguish between longer treatment or addition of the taxane drug. This trial has completed international recruitment of 2890 women who will be carefully followed for 10 years. Australian and New Zealand centers recruited 20% of the women in the trial. After the women have been followed-up for 5 years the results of this trial will be analysed, presented and published and should provide reliable evidence about the potential benefit of adding docetaxel into adjuvant chemotherapy.Read moreRead less