The Role Of A Protease Activated Receptor System In Prostate Cancer Bone Metastasis.
Funder
National Health and Medical Research Council
Funding Amount
$582,204.00
Summary
Prostate cancer is one of the most significant health issues for men. This disease occurs because certain proteins start to function abnormally. Our focus is on a protein called PAR2, present on the surface of prostate cancer cells and bone cells, which we propose helps cancer cells to spread to bone. In our project, we aim to understand how this happens so that we can develop ways to block prostate cancer metastasis to bone.
CHAPERONES IN BREAST CANCER AND ESTROGEN RECEPTOR FUNCTION
Funder
National Health and Medical Research Council
Funding Amount
$256,573.00
Summary
Resistance to hormone therapy in breast cancer is due to adaptations of estrogen signalling mechanisms that result in ERa activation causing growth. So, in the search for new treatments, we are looking for ways to remove ERa from the breast cancer cell. Our study addresses this major issue by focussing on Hsp90 molecular chaperone machinery that is essential for ERa function and in particular immunophilin 'helper' cochaperones that form part of receptor-Hsp90 complexes and fine-tune receptor res ....Resistance to hormone therapy in breast cancer is due to adaptations of estrogen signalling mechanisms that result in ERa activation causing growth. So, in the search for new treatments, we are looking for ways to remove ERa from the breast cancer cell. Our study addresses this major issue by focussing on Hsp90 molecular chaperone machinery that is essential for ERa function and in particular immunophilin 'helper' cochaperones that form part of receptor-Hsp90 complexes and fine-tune receptor responses to hormone. Through a novel mode of action, coumarin-based Hsp90 inhibitors disrupt Hsp90 dimerization causing receptor release and subsequent depletion. We will confirm this novel mechanism for new, high affinity Hsp90 inhibitors and determine which can best interfere with estrogen signalling, either alone or in combination with antiestrogen therapies in the treatment of hormone-dependent cancers. Our study has the potential to pin point the site of action of the immunophilins in ERa to a proline in a region critical for ligand-induced receptoractivation. We will determine the role of the immunophilins and this active-site proline residue in modulating receptor stability and function. Aberrant expression of receptor-associated immunophilins appears linked to endocrine resistance and metastasis in breast cancer. Our study will profile the expression of these chaperones in well defined breast cancer tissue microarrays, and has the potential to identify them as informative biomarkers in the treatment of the disease.Read moreRead less
Breast Cancer has a particular preference to form cancer metastases in bone where its presence is associated with bone destruction that frequently results in significant pain and disability. Bone seems to provide a fertile soil for breast cancer cells that have moved into the blood vessels from the original cancer site in the breast. Once tumour cells have invade bone marrow spaces from the blood vessels they are able to grow and induce the normal cells of the bone marrow to destroy the surround ....Breast Cancer has a particular preference to form cancer metastases in bone where its presence is associated with bone destruction that frequently results in significant pain and disability. Bone seems to provide a fertile soil for breast cancer cells that have moved into the blood vessels from the original cancer site in the breast. Once tumour cells have invade bone marrow spaces from the blood vessels they are able to grow and induce the normal cells of the bone marrow to destroy the surrounding hard bone. This allows the tumour to grow faster. Together these processed create a vicious cycle that contributes to the serious consequences of bone metastases. In this project we will be studying mice with breast cancer to understand what makes the bone marrow such a fertile and receptive site for breast cancer metastasis. In particular, we are looking at how the normal processes of bone renewal and repair contribute to the establishment of cancer in bone. We will use the body's own bone protecting protein, called osteoprotegerin, to test how blocking bone destruction will affect the ability of cancer cells to invade and grow in bone. This study has the potential to change the way bone metastases are treated. Treatment of breast cancer could be significantly improved if the fertile soil of bone could be modified to either block the targeting of breast cancer to bone, or to inhibit its growth there.Read moreRead less
Proteolytic And Non-proteolytic Roles For PSA And Related Kallikrein Serine Proteases In Prostate Cancer Progression
Funder
National Health and Medical Research Council
Funding Amount
$480,128.00
Summary
Prostate cancer is the most frequently occurring cancer in men in Western countries. Prostate cancer metastasis to bone and other organs is the painful end stage of this disease. The level of prostate specific antigen (PSA) in blood is often used as a marker of prostate cancer. PSA is one of 15 related enzymes in the kallikrein family of enzymes, which may be involved in breakdown of the tissue that surrounds cells in the prostate. As prostate cancer metastasis first requires spread from the pri ....Prostate cancer is the most frequently occurring cancer in men in Western countries. Prostate cancer metastasis to bone and other organs is the painful end stage of this disease. The level of prostate specific antigen (PSA) in blood is often used as a marker of prostate cancer. PSA is one of 15 related enzymes in the kallikrein family of enzymes, which may be involved in breakdown of the tissue that surrounds cells in the prostate. As prostate cancer metastasis first requires spread from the primary tumour and out of the prostate, it is possible that high production of these kallikrein enzymes by prosttae cancer cells may increase the ability of these cells to metastasise. In previous work, we have studied prostate cancer cells that we have engineered to make the kallikreins, PSA and kallikrein 4. Those cells that make PSA or kallikrein 4 are more elongated in shape and are better able to move across a porous barrier. Another important change is that these cells stop producing a protein that is usually found on the surface of these cells and is important for helping cells to stay attached to each other. When this protein is lost, these tumour cells no longer stay attached to each other and are more likely to move out of the prostate and spread into other parts of the body. The changes we observed in the cells that produce PSA and kallikrein 4 are typical of these more aggressive cancer cells. In this project, we will look at how PSA and kallikrein 4 cause the cells to undergo these changes. The majority of prostate cancer deaths arise from cancer that has spread from the primary tumour and out of the prostate capsule. This project aims to further understand the causes of prostate cancer spread and metastasis. This is a vital research priority if we are to address the mortality associated with prostate cancer metastasis and may lead to new treatment approaches for advanced metastic prostate cancer.Read moreRead less