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Worldwide, more than one million women are diagnosed with breast cancer every year, making it the most common malignancy of females in the developed world. Approximately one-third of breast cancer patients will have tumours that become resistant to standard chemotherapy, and their tumours may relapse and subsequently metastasise. This is thought to be due to the existence of a small population of drug-resistant cells, which may initiate and maintain the tumour. The cells have been termed ‘breast cancer stem cells’ and may originate from normal breast stem cells. The purpose of this project is to understand how healthy mammary stem cells are maintained in the breast and how this process goes awry in breast cancer. We will do this by studying a group of proteins known as “epigenetic modifiers”, which instruct cell identity and behaviour. This knowledge will aid in the earlier detection of tumours and in design and development of novel therapeutic strategies for patients with advanced and metastatic disease.

When diagnosed with breast cancer women have a lot of things to think about. For younger women, cancer treatment can reduce a woman’s ability to have children in the future. This may add to the worry about the cancer, especially if women have not yet finished their families. Research has shown that some women will make choices based on whether they can have children later. This is why it is very important that women know what the side-effects of cancer treatment are. Since there are steps that women can take to increase their chances of having a child later. To do this, they need to know about their options and they need this information early.

It can be difficult for women to make decisions about which treatment is best for them. If people are not given good-quality information they may regret the choices made. This is why it is important that we give women the information they need to make the best choice for them. This study aims to create and give women in this situation information that is easy to get hold of and to understand. It will test how helpful the information is in helping women to make decisions about what they can do to raise the chances of having a baby at a later date. It is hoped that this will help make these decisions easier. We will also look at how this information can be easily accessed by women as a part of their medical care.

Advances in breast cancer treatment have improved patient outcomes dramatically, however breast cancer is still responsible for an unacceptable number of deaths. A significant number of patients do not respond to standard treatments, or become resistant to these treatments over time. New approaches are needed to reduce mortality due to breast cancer.

Cancer cells, including breast cancer cells, require alterations in metabolism to support their rapid growth and survival. Findings ways to alter cancer metabolism is a strategy to not only slow cancer progression, but also sensitise cancer to existing treatments. We have evidence that a family of enzymes that alter DNA structure and turn on cancer metabolism genes are involved in breast cancer. This project will examine the role of these enzymes in breast cancer metabolism, survival and sensitivity to existing chemotherapy treatments. In addition, this project will determine whether inhibiting these enzymes enhances responses to existing treatments, as well as whether these enzymes predict patient survival and treatment outcomes.

This research proposal will increase our understanding of how breast cancer cells alter their metabolism to help them survive and could identify a new treatment strategy that would sensitise breast cancer to existing breast cancer treatments.

Exercise can reduce the risk of developing breast cancer, and improve survival amongst women diagnosed with the disease. Despite this knowledge, the majority of Australian women do not participate in sufficient exercise. Further, how the eight or nine hours of daily sitting time accumulated by Australian women affects their breast cancer risk is unknown. Given what we know about the biology of breast cancer, it is likely that sitting time also contributes to risk.

The proposed research will address two themes: breast cancer prevention, and breast cancer survivorship. Using data collected by existing studies I will examine how the type, duration, intensity and frequency of exercise and sitting time relate to breast cancer. A new study (part of a much larger project being undertaken by Cancer Council Victoria – the ABC Study) will collect accurate information on the exercise and sitting time patterns of approximately 1,000 postmenopausal women, by using small devices called accelerometers. This will help us to understand how exercise and sitting time affect breast cancer risk. Another new study will investigate whether the use of wearable activity monitors (such as the Fitbit®) can increase breast cancer survivors’ exercise and reduce their sitting time.

The proposed research will enable us to provide more specific advice to women about how much, and what type of, exercise they should be doing to prevent breast cancer, or to improve their survival after diagnosis. It will also allow us to give guidance on how much sitting is can be safely done each day.

This request for infrastructure support will enable lifepool to maintain operation and expand to recruit women from other states in Australia. The national lifepool cohort will provide data and biospecimens to enable laboratory based, clinical and psychosocial research into better understanding breast cancer. A key strength of lifepool is the capacity to support research aimed at understanding breast cancer risk factors; in particular through supporting research which gathers an evidence base for design of breast cancer screening strategies tailored to personal risk factors. Lifepool can provide DNA and tumour samples with extensive clinical and outcome information in a group of women gathered from across the Australian population. Lifepool engages with women across the spectrum of breast cancer risk: Those who have not been diagnosed and are at ‘population’ risk, women recently diagnosed through the BreastScreen program and women from high risk families with and without a breast cancer diagnosis. Close collaboration across medical research institutes, breast cancer clinicians, BreastScreen services, epidemiologists and other experts in public health as well as active and committed representation from breast cancer advocacy groups has produced a resource of enormous potential in the shared aim of reducing the burden on breast cancer on the community.

Our team investigates the prediction and response of Head and Neck cancer patients to a monoclonal antibody therapy called Cetuximab. Cetuximab recognises ErbB1 (Her 1/EGFR) protein when it is present on the surface of cancer cells, however it is not effective in all patients. We have discovered a way to make Cetuximab effective for a larger number of patients. Moreover, we found this approach also works for Herceptin, the monoclonal antibody which recognises ErbB2 (Her2) protein on breast cancer cells. We found that by moving ErbB1(Her1) and/or ErbB2 (Her2) receptors to the tumour cell surface, they are able to interact with the antibody therapies and generate a much better immune response, which kills even normally resistant cancer cells. Crucially, there are drugs that have been in clinical use for thirty years that can do just this. These drugs (Stemetil, Haloperidol and CPZ) are commonly used as anti-psychotics and anti-nausea treatments, and have been used in advanced cancer palliative care. We want to determine which of these compounds best promotes Herceptin-mediated tumour cell killing in HER2 cells in order to move forward to breast cancer patient trials. We also found that we could get enough ErbB1 (Her1) and ErbB2 (Her2) onto the surface of triple negative breast cancer cells to allow Herceptin and Cetuximab mediated killing. We are starting clinical trials in Head and Neck SCC patients and this proposal covers the work necessary to run a similar trial in breast cancer patients with Her2 positive tumours or triple negative tumours.

A significant portion of breast cancers remain incurable due to high-risk molecular changes, such as overproduction of HER2 protein. HER2-enhanced breast cancers (HEBC) grow fast, spread early and often relapse quickly when treated. Currently, the only useful approach to slow down HEBC is by inhibiting HER2, which is believed to be a dominant “driver” of these tumours. However, HER2-inhibitory drugs fail to suppress over 70% of HEBC, which are either natively resistant or adapt gradually to become HER2-independent. These facts suggest that HER2-independent mechanisms also contribute significantly to aggressive features of HEBC, including therapy resistance and the propensity to spread into various organs that are directly linked to patient death. Furthermore, an intact immune system has been recently indicated critical to counteract progressive HEBC. So better understanding these mechanisms is fundamentally important to enrich knowledge of HEBC biology and further potentiate better treatment.

With a view to improving HEBC treatment and outcome, our research aims to uncover alternative factors that stimulate growth and spread of HEBC cells by using the latest cutting-edge technologies in molecular cancer research. Additional research focuses include systematic investigation of mechanisms conferring resistance to anti-HER2 therapies or those exploited by tumours to mislead the immune system. Because the targeted disease traits are directly responsible for patient death and inferior quality of life, our discoveries are expected to provide new answers to the clinically critical questions in HEBC, which could be translated into more efficacious therapies. Further, the new methodologies introduced by this research will benefit other breast cancer research.

Double reading of mammography images, where two radiologists independently read the same patient images is current practice in the Breast Screening service in Australia. Compared with single reads, the double read strategy improves outputs from breast screening programs, e.g. if a woman’s cancer is missed by one radiologist, the second radiologist may pick it up by thus leading to improved cancer detection rates. Unfortunately however double reading only works if paired radiologists complement each other, i.e. they do not make the same type of error, therefore sophisticated matching is required. Such sophisticated matching has never been implemented due to historic reasons: since mammographic films can only be physically stored at one location (often where they are produced), matching of radiologists has been performed out of geographic convenience rather than maximizing diagnostic potential. However in 2014, almost all mammographic images are produced, transmitted and stored electronically (digitally) meaning that a woman’s images can be read by anyone, anywhere (regardless of where they are produced). This means that radiologists can be matched on reading characteristics and individual errors rather than geography.

By bringing together scientists from Australia and the US we will:

Streamlining the double reading strategy, will result in substantial benefits for the 1.6 million Australian women who participate in breast screening over a two-year cycle, as well as the millions who undergo mammography world-wide each year.

This project aims to identify whether patients can be selected for a certain type of therapy by non-invasively imaging the expression of the glutathione s-transferase enzyme. Another potential application of this project lies in the early detection of treatment response and to monitor this in a non-invasive manner. This is particularly important in breast cancer, since chemotherapy and targeted agents may be used, but can have side effects, and not all patients respond to treatment. Early identification of the molecular signature of a breast cancer may allow selection of a more appropriate treatment, thus improving patient outcome.

More than 90% of breast cancer-related death is associated with metastatic cancer relapse. Relapse can occur from few months to several years following the treatment of the primary tumour, and is often characterised by tumour growth at multiple locations in the body. Early detection of such growth dramatically increases the effectiveness of further cancer treatment. Since at the early stage of metastasis new tumours are small, their detection is very difficult. Tumour growth is accompanied by release of tumour DNA into the surrounding tissues and blood, and so the ability to detect tumour DNA in blood provides a very attractive avenue for breast cancer diagnostics. However the current methods for detection of tumour DNA require complex equipment and are not suitable for continuous monitoring. Therefore we propose to develop a simple diagnostic test that identifies tumour DNA in the patient’s blood. Conceptually this test is similar to the one used for measuring the blood sugar in diabetic patients. The test is based on semiconductor-like proteins developed in CI Alexandrov’s laboratory. These proteins could be engineered to selectively recognize the tumour DNA and pass this information to a detector connected to a smart phone. Such test will improve the treatment outcome and quality of life of breast cancer patients.