Exploring A New Way To Overcoming Endocrine Resistance In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$441,764.00
Summary
Despite significant improvements in long-term outcome with the use of endocrine therapy (such as tamoxifen and letrozole), breast cancer remains the most common cause of cancer-related death amongst Australian women. A major clinical problem limiting the effectiveness of endocrine therapy is tumour resistance, either intrinsic or acquired. Indeed, about half of patients immediately fail to respond to the treatment, while in the initially responding patients the tumours ultimately progress to res ....Despite significant improvements in long-term outcome with the use of endocrine therapy (such as tamoxifen and letrozole), breast cancer remains the most common cause of cancer-related death amongst Australian women. A major clinical problem limiting the effectiveness of endocrine therapy is tumour resistance, either intrinsic or acquired. Indeed, about half of patients immediately fail to respond to the treatment, while in the initially responding patients the tumours ultimately progress to resistance to the drug leading to the disease relapse. Therefore, it is imperative to better understand the mechanisms responsible for the resistance and to explore new strategies that overcome this clinical problem in order to prolong the overall survival of patients with breast cancer. Our recent work have shown that a recently-identified enzyme, termed sphingosine kinase, plays an important role in promoting breast cancer cell growth. We also found that cells that have a high level of the enzyme had bad outcomes in response to anti-estrogen drug, tamoxifen. Thus this project seeks to identify the role of this enzyme in contributing towards drug resistance, and test if inhibition of this enzyme could improve and-or restore the drug response in breast cancer. It will ultimately pave a new way to overcoming the drug resistance for improving the treatment and prevention of breast cancer.Read moreRead less
Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility t ....Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility that it plays an important role in breast cancer cell proliferation. To better understand how estrogen signals in breast cancer and identify proteins that bind to SRA in cancer cells, we established a collaboration with the O'Malley group at Baylor College of Medicine in Texas (who discovered SRA). We have identified several novel SRA-binding proteins, each of which plays an important role to regulate estrogen and androgen action. Up to this point, we have used a model that has enabled proof of principle studies in the same cancer cells from which SRA was discovered (non-breast or prostate cancer). However, we now need to carefully study the role of these proteins in cancer cells relevant to breast and prostate cancer. Thus, we plan to investigate how these proteins interact with SRA, how they influence nuclear receptor activity and breast and prostate cancer cell proliferation, examine their role in activating other pathways of cell growth in cancer cells, assay the levels of each protein in a series of human breast cancer specimens and solve the physcial 3-D structure of these proteins complexed to the SRA RNA. This work will provide novel insight into several key areas of hormone action in breast and prostate cancer. We hope to identify new markers that can be used for improved diagnosis and for prognosis, and provide structural information for the development of novel therapeutics.Read moreRead less
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