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News Article | December 9, 2016
Site: www.eurekalert.org

An international team of researchers involving the University of Adelaide is tackling the controversy over what some scientists consider to be a "harmful" hormone, arguing that it could be a game changer in the fight against recurring breast cancers that are resistant to standard treatments. The controversy centers on the different effects in women of the naturally occurring sex steroid hormone progesterone compared with synthetic forms (i.e. progestins) designed to mimic its actions. Some, but not all, progestins have been linked with increased breast cancer risk when used in menopausal hormone therapy, leading to concerns in the scientific community about the use of these drugs. However, in a paper now published online ahead of print in the prestigious journal Nature Reviews Cancer, an international team - involving the University of Adelaide's Dame Roma Mitchell Cancer Research Laboratories (DRMCRL) and the Cancer Research UK (CRUK) Cambridge Institute - highlights that progesterone when used in menopausal hormone therapy does not increase breast cancer risk . Indeed, progesterone may have an important role to play in the safe and effective management of recurring breast cancer. "Breast cancer arises because of abnormal hormone activity, with about 75% of these cancers being driven by the estrogen receptor. Unfortunately, despite good initial responses in many women, drug resistance is common, usually leading to a recurrence and lethal spread of the disease," says Professor Wayne Tilley, Director of the Dame Roma Mitchell Cancer Research Laboratories at the University of Adelaide, and a lead author of the paper. "Moreover, current hormonal treatments that target the estrogen receptor in breast cancer, especially specific inhibitors that block estrogen production, can markedly impact quality of life, often leading women to stop taking the drugs or change their treatment." Professor Tilley says the team's recent studies, including landmark research already published in Nature, suggest that a safe way of improving treatment - without having a deleterious effect on quality of life - does exist, through the use of natural progesterone and certain other progestins. "There is a natural 'crosstalk' between estrogen and progesterone receptors that we strongly believe can be exploited," he says. "In particular, progesterone can reprogram estrogen action in the breast in a way that results in estrogen receptor action improving breast cancer outcomes. Because of this unique interaction of the two natural female sex hormones in the breast, we see great potential benefits in adding progesterone to existing drugs that target the estrogen receptor, thereby helping to switch off the growth of cancer cells. "This gives us a unique opportunity to develop a new hormonal treatment which, when used in conjunction with the current standard of care, would enhance and improve outcomes for many breast cancer patients. "Unfortunately, there are some serious misconceptions about the role of progesterone in cancer biology that have so far prevented it from being widely used in the management of breast cancer. We hope to change that thinking," Professor Tilley says. The team, which is highly regarded for its research into both breast and prostate cancer, believes this new paper will have a global impact on clinical, scientific and public opinion on the relative risks and benefits of using progesterone and certain progestins to treat women with breast cancer. "Ultimately, we hope this work will eventually result in saving women's lives," Professor Tilley says. The real proof will come from two new clinical trials being conducted by the international team, with patients being recruited for the studies in the UK early next year. One trial in collaboration with a UK group at the University of Liverpool will test the potential benefit of combining progesterone treatment with the breast cancer drug Tamoxifen in premenopausal women with breast cancer. A second trial involving postmenopausal women with breast cancer has been initiated by collaborators at the CRUK Cambridge Institute and will evaluate whether a particular progestin, Megace, provides added therapeutic benefit when combined with a current estrogen receptor target treatment, compared to the target treatment alone. Professor Tilley says the team's research has recently resulted in several substantial new sources of funding for Adelaide's Dame Roma Mitchell Cancer Research Laboratories to continue their ground-breaking research in breast cancer. These include: Professor Tilley was also awarded another NHMRC Project Grant of more than $946,000 to develop new and smarter therapies to inhibit the androgen receptor, which is the key driver of prostate cancer growth. "Resistance to current therapies that target the androgen receptor is the main cause of lethal prostate cancer. Researchers in the Dame Roma Mitchell Cancer Research Laboratories are developing and testing a new drug that is effective against the androgen receptor in preclinical models of treatment resistant prostate cancer. It is hoped that this new drug will inhibit the growth of tumors that currently kill approximately 3,300 men in Australia each year," he says. "Our recent funding success will ensure that South Australian research into breast and prostate cancer remains at the forefront of improving the health and quality of life for women and men afflicted by these diseases. "More importantly, this funding will make significant inroads into improving survival rates for patients who develop resistance to current hormonal treatments for these cancer types, which are major killers of Australian women and men," Professor Tilley says.


Pertega-Gomes N.,CRUK Cambridge Institute | Vizcaino J.R.,Centro Hospitalar do Porto | Felisbino S.,São Paulo State University | Warren A.Y.,University of Cambridge | And 10 more authors.
Oncotarget | Year: 2015

Monocarboxylate Transporter 2 (MCT2) is a major pyruvate transporter encoded by the SLC16A7 gene. Recent studies pointed to a consistent overexpression of MCT2 in prostate cancer (PCa) suggesting MCT2 as a putative biomarker and molecular target. Despite the importance of this observation the mechanisms involved in MCT2 regulation are unknown. Through an integrative analysis we have discovered that selective demethylation of an internal SLC16A7/MCT2 promoter is a recurrent event in independent PCa cohorts. This demethylation is associated with expression of isoforms differing only in 5'-UTR translational control motifs, providing one contributing mechanism for MCT2 protein overexpression in PCa. Genes co-expressed with SLC16A7/MCT2 also clustered in oncogenic-related pathways and effectors of these signalling pathways were found to bind at the SLC16A7/MCT2 gene locus. Finally, MCT2 knock-down attenuated the growth of PCa cells. The present study unveils an unexpected epigenetic regulation of SLC16A7/MCT2 isoforms and identifies a link between SLC16A7/MCT2, Androgen Receptor (AR), ETS-related gene (ERG) and other oncogenic pathways in PCa. These results underscore the importance of combining data from epigenetic, transcriptomic and protein level changes to allow more comprehensive insights into the mechanisms underlying protein expression, that in our case provide additional weight to MCT2 as a candidate biomarker and molecular target in PCa.


PubMed | CRUK Cambridge Institute, Centro Hospitalar do Porto, University of Cambridge and São Paulo State University
Type: Journal Article | Journal: Oncotarget | Year: 2015

Monocarboxylate Transporter 2 (MCT2) is a major pyruvate transporter encoded by the SLC16A7 gene. Recent studies pointed to a consistent overexpression of MCT2 in prostate cancer (PCa) suggesting MCT2 as a putative biomarker and molecular target. Despite the importance of this observation the mechanisms involved in MCT2 regulation are unknown. Through an integrative analysis we have discovered that selective demethylation of an internal SLC16A7/MCT2 promoter is a recurrent event in independent PCa cohorts. This demethylation is associated with expression of isoforms differing only in 5-UTR translational control motifs, providing one contributing mechanism for MCT2 protein overexpression in PCa. Genes co-expressed with SLC16A7/MCT2 also clustered in oncogenic-related pathways and effectors of these signalling pathways were found to bind at the SLC16A7/MCT2 gene locus. Finally, MCT2 knock-down attenuated the growth of PCa cells. The present study unveils an unexpected epigenetic regulation of SLC16A7/MCT2 isoforms and identifies a link between SLC16A7/MCT2, Androgen Receptor (AR), ETS-related gene (ERG) and other oncogenic pathways in PCa. These results underscore the importance of combining data from epigenetic, transcriptomic and protein level changes to allow more comprehensive insights into the mechanisms underlying protein expression, that in our case provide additional weight to MCT2 as a candidate biomarker and molecular target in PCa.


Severson T.M.,Netherlands Cancer Institute | Peeters J.,Agendia Inc. | Majewski I.,Netherlands Cancer Institute | Majewski I.,Walter and Eliza Hall Institute of Medical Research | And 17 more authors.
Molecular Oncology | Year: 2015

Triple negative (TN) breast cancers make up some 15% of all breast cancers. Approximately 10-15% are mutant for the tumor suppressor, BRCA1. BRCA1 is required for homologous recombination-mediated DNA repair and deficiency results in genomic instability. BRCA1-mutated tumors have a specific pattern of genomic copy number aberrations that can be used to classify tumors as BRCA1-like or non- BRCA1-like. BRCA1 mutation, promoter methylation, BRCA1-like status and genome-wide expression data was determined for 112 TN breast cancer samples with long-term follow-up. Mutation status for 21 known DNA repair genes and PIK3CA was assessed. Gene expression and mutation frequency in BRCA1-like and non- BRCA1-like tumors were compared. Multivariate survival analysis was performed using the Cox proportional hazards model. BRCA1 germline mutation was identified in 10% of patients and 15% of tumors were BRCA1 promoter methylated. Fifty-five percent of tumors classified as BRCA1-like. The functions of genes significantly up-regulated in BRCA1-like tumors included cell cycle and DNA recombination and repair. TP53 was found to be frequently mutated in BRCA1-like (P < 0.05), while PIK3CA was frequently mutated in non- BRCA1-like tumors (P < 0.05). A significant association with worse prognosis was evident for patients with BRCA1-like tumors (adjusted HR = 3.32, 95% CI = 1.30-8.48, P = 0.01). TN tumors can be further divided into two major subgroups, BRCA1-like and non-BRCA1-like with different mutation and expression patterns and prognoses. Based on these molecular patterns, subgroups may be more sensitive to specific targeted agents such as PI3K or PARP inhibitors. © 2015 The Authors.


Chabbert C.D.,Genome Biology Unit | Chabbert C.D.,CRUK Cambridge Institute | Steinmetz L.M.,Genome Biology Unit | Steinmetz L.M.,Stanford University | Klaus B.,Genome Biology Unit
PeerJ | Year: 2016

The genome-wide study of epigenetic states requires the integrative analysis of histone modification ChIP-seq data. Here, we introduce an easy-to-use analytic framework to compare profiles of enrichment in histone modifications around classes of genomic elements, e.g. transcription start sites (TSS). Our framework is available via the user-friendly R/Bioconductor package DChIPRep. DChIPRep uses biological replicate information as well as chromatin Input data to allow for a rigorous assessment of differential enrichment. DChIPRep is available for download through the Bioconductor project at http://bioconductor.org/packages/DChIPRep. © 2016 Chabbert et al.


PubMed | CRUK Cambridge Institute, Stanford University and Genome Biology Unit
Type: | Journal: PeerJ | Year: 2016

The genome-wide study of epigenetic states requires the integrative analysis of histone modification ChIP-seq data. Here, we introduce an easy-to-use analytic framework to compare profiles of enrichment in histone modifications around classes of genomic elements, e.g. transcription start sites (TSS). Our framework is available via the user-friendly R/Bioconductor package DChIPRep. DChIPRep uses biological replicate information as well as chromatin Input data to allow for a rigorous assessment of differential enrichment. DChIPRep is available for download through the Bioconductor project at http://bioconductor.org/packages/DChIPRep. Contact. DChIPRep@gmail.com.


PubMed | CRUK Cambridge Institute, Agendia Inc., Lund University and Netherlands Cancer Institute
Type: Journal Article | Journal: Molecular oncology | Year: 2015

Triple negative (TN) breast cancers make up some 15% of all breast cancers. Approximately 10-15% are mutant for the tumor suppressor, BRCA1. BRCA1 is required for homologous recombination-mediated DNA repair and deficiency results in genomic instability. BRCA1-mutated tumors have a specific pattern of genomic copy number aberrations that can be used to classify tumors as BRCA1-like or non-BRCA1-like. BRCA1 mutation, promoter methylation, BRCA1-like status and genome-wide expression data was determined for 112 TN breast cancer samples with long-term follow-up. Mutation status for 21 known DNA repair genes and PIK3CA was assessed. Gene expression and mutation frequency in BRCA1-like and non-BRCA1-like tumors were compared. Multivariate survival analysis was performed using the Cox proportional hazards model. BRCA1 germline mutation was identified in 10% of patients and 15% of tumors were BRCA1 promoter methylated. Fifty-five percent of tumors classified as BRCA1-like. The functions of genes significantly up-regulated in BRCA1-like tumors included cell cycle and DNA recombination and repair. TP53 was found to be frequently mutated in BRCA1-like (P<0.05), while PIK3CA was frequently mutated in non-BRCA1-like tumors (P<0.05). A significant association with worse prognosis was evident for patients with BRCA1-like tumors (adjusted HR=3.32, 95% CI=1.30-8.48, P=0.01). TN tumors can be further divided into two major subgroups, BRCA1-like and non-BRCA1-like with different mutation and expression patterns and prognoses. Based on these molecular patterns, subgroups may be more sensitive to specific targeted agents such as PI3K or PARP inhibitors.


News Article | September 7, 2016
Site: www.nature.com

The ability of an organ's stem cells to generate new tissue over time — the cells' generative capacity — determines how prone that organ is to cancer. Scientists have debated the relative importance of factors that contribute to an organ's cancer risk, including 'intrinsic' factors such as the number of stem-cell divisions and 'extrinsic' factors that cause tissue and DNA damage. To compare these factors, Richard Gilbertson at the CRUK Cambridge Institute, UK, Arzu Onar-Thomas at St Jude Children's Research Hospital in Memphis, Tennessee, and their colleagues studied stem cells called Prom1+ cells with varying levels of generative capacity in different organs in mice of various ages. The authors introduced key cancer-causing mutations into the cells, then looked for tumour growth in the organs. The team found that cancer risk correlated closely with the generative capacity of the Prom1+ cells. In liver tissue, cancer mutations alone did not cause cancer — tissue injury significantly increased cancer susceptibility. The authors propose that several factors contribute to a 'perfect storm' of tumour growth: mutated stem cells and extrinsic factors that trigger cell proliferation.

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