RESEARCH WE SUPPORT

Weight management has an important role in improving the health and wellbeing of women after treatment for breast cancer.

This research will focus on how best to support women who have been diagnosed with breast cancer to make lifestyle changes and lose weight. It will include the first Australian trial and one of a few internationally to evaluate a weight loss intervention, delivered via telephone, for overweight women after treatment for breast cancer.

This study will also help to understand the biological mechanisms by which weight loss may improve outcomes in women with breast cancer. The results will be used to integrate weight management into standard follow-up care for women with breast cancer.

The prognosis for women with metastatic breast cancer is poor. The precise mechanisms of breast cancer spread are still unclear.

This study focuses on members of a cell protein family called BCL-2, which regulate apoptosis, a process of cell death that is frequently impaired in cancer cells.

Studies of various cancers have reported a link between expression of BCL-2 family members and patient outcome. This observation has led to the hypothesis that some of these proteins may be involved in the development and spread of breast cancer.

This research will help to better understand breast cancer progression and to design improved treatments.

To survive, grow and invade the body, all breast cancer cells must learn how to avoid cell death. We have little understanding of why proteins that promote cell death fail to respond during breast cancer treatment. This research will increase understanding of how pro-death proteins operate in the normal breast and, more importantly, how they can be activated during treatment of aggressive breast cancer.

Using lessons learnt from the treatment of cancers in other tissues, we will search for new and improved therapies that kill breast cancer cells while limiting toxicity to normal tissues.

The successful outcome of this fellowship will result in the discovery of new ways to kill breast cancers that, with further clinical development, will result in improved patient outcomes.

Triple negative is a term used to describe types of breast cancer that do not have any of the three receptors commonly found on breast cancer cells: oestrogen receptors, progesterone receptors and human epidermal growth factor receptor 2.

Triple negative breast cancer presents a major clinical problem as it is generally associated with poor outcome and increased risk of recurrence, and it resists therapies that target hormone receptors, such as tamoxifen and herceptin.

This research will identify new cancer genes that are implicated in triple negative breast cancer and establish their role in cancer progression. It will pave the way to develop reliable tools to diagnose triple negative breast cancer and determine prognosis, as well as develop patient-tailored drugs.

This research uses data from large international studies to improve our understanding of the genetic and non-genetic factors that affect breast cancer risk. This will enhance our ability to predict risk for an individual woman, and to understand which interventions might best reduce that risk.

A web-based breast cancer risk assessment and decision aid tool will be developed and tested so that the findings of the research can be translated into clinical practice. This tool will help GPs, breast surgeons and other clinicians to accurately assess and effectively manage breast cancer risk using a shared decision-making approach with their patients.

The ultimate goal of this research is to implement routine, accurate breast cancer risk prediction and risk management across the Australian community, thereby reducing the burden of this disease.

This research addresses gaps in evidence in mammography screening of women with an average risk of breast cancer and in women who have had breast cancer and are at increased risk of another breast cancer but have received little attention in screening research.

This research, based in an international trial, will compare the accuracy and outcomes of screening using integrated 2D/3D mammography with standard (2D) mammography to determine whether this new technology improves the rate and accuracy of breast cancer detection.

In a separate project focusing on women who have had breast cancer, the research will identify factors that may increase the risk of an interval cancer (a cancer that is missed at annual mammography).

The findings from this research will guide women and clinicians about the need for enhanced surveillance in women with history of breast cancer who are at increased risk of an interval breast cancer.

One of the strongest risk factors for the development of lobular breast cancer is having a close relative with the disease. There have been some advances in understanding the genetic factors that underlie this susceptibility, but these known genetic factors only explain a very small proportion of the overall familial effect.

This research will build upon prior research from this team, as well as international research resources, new technology and supercomputing to identify lobular breast cancer susceptibility genes.

Co-funded by NBCF and Cancer Australia

Triple negative is a term used to describe types of breast cancer that do not have any of three receptors commonly found on breast cancer cells: oestrogen receptors, progesterone receptors and human epidermal growth factor receptor (HER2].

Generally, these types of breast cancers that often occur in younger women do not respond well to current targeted therapies, are more aggressive, and are associated with higher mortality rates.

Recently, clinical attention has focused on targeting the androgen receptor to treat triple negative breast cancer. While this may be a promising approach, we need to know more about how androgens act in these cancers.

This project will determine which triple negative breast cancers are most likely to respond to therapeutic approaches that target androgen receptor.

Co-funded by NBCF and Cancer Australia

The new targeted cancer agents are a major medical advance, but they come with a high price tag.

Importantly, these medicines are not always used in everyday clinical practice the same way they are used in clinical trials. This project will provide critical evidence about real-world resource use and long-term outcomes of high-cost targeted cancer therapies.

We will use routinely collected health care data to examine the use of cancer medicines and medical services, and the effectiveness and costs of targeted medicines outside clinical trial conditions. Currently these comprehensive data are not readily available to policy agencies to support decisions about what medicines should be subsidised.

Co-funded by NBCF and Cancer Australia

Breast cancer is a very complex disease which may consist of up to 10 different subtypes. It is now recognised that breast cancer arises in stem cells – individual cells in the breast which have the ability to develop into any different cell type – or their progeny (called luminal progenitor cells).

This research will generate new mouse models in which certain molecular pathways are overactivated to test their potential to generate subtypes of human breast cancer.

The research will visualise breast cells in their normal tissue environment to better understand how breast tumour cells are able to escape from normal cellular control, invade into nearby tissue and then spread throughout the body.

This research is co-funded by NBCF and Cure Cancer Australia Foundation.

While inherited faults in two genes, BRCA1 and BRCA2, are known to be important in the development of hereditary breast cancer, the genetic cause of most familial breast cancer is not known.

The aim of this study is to identify other genes that cause a predisposition to breast cancer in families affected by the disease.

The research will analyse the genetics of 125 high-risk breast cancer families as well as examine about 3000 BRCA1/2 mutation-negative familial breast cancer cases and 3000 controls to determine the contribution of rare, harmful genetic mutations to breast cancer risk. Identification of new genes that predispose to the development of breast cancer will improve risk assessment, genetic counselling and management for individuals in high-risk breast cancer families.

Resistance to endocrine (anti-hormone) therapy is a major clinical problem in breast cancer. Understanding the molecular basis of anti-hormone resistance will help a large number of women with breast cancer.

Epigenetics, which means ‘above genetics’, is concerned with chemical tags on the DNA or on proteins called histones that attach to the DNA. These chemical tags provide instructions to switch genes on or off. Epigenetics is inherited but it can change during normal developmental processes, such as puberty and pregnancy. Importantly, these chemical tags can also change in certain diseases, such as cancer.

The Elf5 gene has recently been identified as playing a key role in the development of anti-hormone resistance. Elf5 expression can be regulated by epigenetics.

Epigenetic drugs are emerging as a new hope for cancer patients as an alternative to conventional chemotherapy as they are able to revert epigenetic changes, allowing cancerous cells to return to a more normal, healthy state.

The expected outcome of this work will show the critical involvement of Elf5 epigenetic regulation in hormone-resistant breast cancer and will provide potential to explore a new approach to combined therapies through epigenetic drugs.

This research is co-funded by NBCF and Cure Cancer Australia Foundation.

DNA damage repair genes are highly expressed in aggressive high-grade breast cancers. In particular we have found high levels of the DNA damage repair protein, RAD51, in breast cancer that has spread beyond the breast (metastatic breast cancer).

Reducing RAD51 levels delays the spread of cancer to the brain, bone and lung in mice implanted with mouse or human breast cancer cells. Dr Wiegmans hypothesises that as well as its natural DNA repair activity, RAD51 helps metastatic cells to survive.

This research aims to decipher RAD51’s role in the spread of breast cancer to develop effective therapies against aggressive metastatic disease.

Despite significant improvements in survival from breast cancer over the past two decades, there remains an urgent need to develop effective preventative strategies, particularly for women who are at high risk of inherited disease.

This project aims to develop a novel strategy using a drug called denosmab, which has recently been approved to treat osteoporosis and bone metastasis in breast cancer.

Denosmab is an antibody that targets and inhibits the actions of a protein called RANK-L, which is involved in bone regulation. Previous work from Professor Jane Visvader’s laboratory has shown that inhibition of RANK-L can also inactivate breast stem cells, which are the likely culprits in breast cancer. This observation has led Professor Visvader to hypothesise that using denosmab to inhibit RANK-L may prevent breast cancer in people at high risk of developing the disease, such as those carrying mutations in the two known breast cancer genes, BRCA1 and BRCA2.

This project will not only increase understanding of the cellular factors driving breast cancer development, particularly in high-risk women, but will provide data needed to develop denosmab as an medication to prevent breast cancer that runs in families.

This project aims to study new ways to reduce the lifetime risk of developing breast cancer by exploring the protective effects of pregnancy.

It is well established that women who have had a full-term pregnancy before the age of 25 are at a significantly reduced lifetime risk of developing breast cancer. However, while several theories have been proposed, it is not known how pregnancy protects against breast cancer.

Associate Professor Ingman’s concept is that early pregnancy elicits a ‘memory’ in the spinal cord that changes how breast tissue functions, potentially making the tissue more resistant to cancer.

Associate Professor Ingman will study changes in spinal cord cells that are induced by pregnancy and lactation using mouse models, and investigate how these changes affect the development of breast cancer.

The immune system has the potential to both kill tumour cells and support their growth. This project is focused on the role that the immune system plays in breast cancer, with the aim of harnessing its tumour-killing capacity as a new way to treat breast cancer.

A breast tumour is typically made up of cancerous cells as well as non-cancerous cells, including immune cells. Initially, immune cells both within the tumour and circulating in the body restrict the growth of tumours. However, some breast cancers are able to change the function of these immune cells to promote tumour growth and spread to other organs and tissues in the body. This allows secondary cancers or metastases to form, which eventually can lead to death.

It is thought that immune cells, which come from bone marrow stem cells, move directly from the bone marrow to the tumour. Dr Andreas Möller is challenging this theory. He aims to show that immune cells are ‘educated’ by signals from the breast tumour, causing them to move to the breast tumour and promote growth and spread.

Dr Möller will examine the accumulation and education of tumour-promoting immune cells, as well as investigate what happens to tumour growth and spread when these cells are selectively depleted.

Treatment options for patients with advanced breast cancer are extremely limited. If successful, this study could pave the way for new and highly targeted therapies against specific components of the immune system, with potential to slow disease progression and reduce the burden of metastatic disease.

A major clinical problem in breast cancer treatment is ensuring the success of surgery to remove a breast lump and nearby cancerous tissue (a lumpectomy).

The amount of tissue removed in a lumpectomy is quite small, so women who have a lumpectomy can have better cosmetic outcomes and quality of life compared with those who have the whole breast removed (a mastectomy). However, one in five women need a second operation if pathology tests after surgery show that the lumpectomy has not removed all the cancerous tissue. This is not only distressing for the patient; it can increase the chance of complications and reduce their quality of life.

Professor David Callen aims to develop a unique approach for detecting the exact margins of tumour tissue at the time of first surgery. This technique will use photonics, a ground-breaking technology using micro optical fibres to detect markers of cancer.

This study, which brings together physicists, breast cancer researchers and breast surgeons, has the potential to be developed into a diagnostic tool for use in needle biopsies and assessment of lymph node involvement.

While anti-hormone based therapies, such as tamoxifen and arimidex, have significantly enhanced survival for patients with hormone-responsive (ER-positive) breast cancer, many women who initially do well on the drugs develop drug resistance, which leads to cancer recurrence.

This project aims to develop a new class of drugs to treat ER-positive breast cancer that is more effective and minimises the development of drug resistance.

A new type of drug called BH3 mimetics is showing promise in treating some blood cancers. These drugs target an ‘Achilles heel’ of the cancer by neutralising a key pathway involving a protein called BCL2 that helps to keep tumour cells alive. In some leukaemias, BCL2 helps cancer cells to survive by making them more resistant to chemotherapy. Early studies suggest that inhibiting BCL2 using BH3 mimetics can flip a tumour control switch from ‘life’ to ‘death’, thereby eradicating the cancer.

High levels of BCL2 protein are found in most ER-positive breast cancers, raising the possibility that BH3 mimetics combined with anti-hormone therapies could be effective in treating breast cancer and overcoming drug resistance.

Professor Geoffrey Lindeman will use mouse models of ER-positive breast cancer to test the anti-cancer effectiveness of BH3 mimetics alone and in combination with tamoxifen. He will also explore combining BH3 mimetics with other breast cancer therapeutics such as herceptin. If successful, this should lead to early clinical trials of BH3 mimetics in breast cancer patients.

This project aims to develop a novel strategy for treating breast cancer that has spread to the bones (bone metastasis) by harnessing the anti-cancer properties of the immune system.

Bone metastasis occurs in more than 75% of patients with advanced breast cancer. It causes bone destruction, which can lead to increased risk of fracture, chronic pain and even paralysis. There are few treatments for bone metastasis in patients with breast cancer, so new and safe treatments are urgently required.

Professor Andreas Evdokiou and his team plan to use the potent tumour-killing properties of a subset of immune cells called gamma delta T cells. These cells circulate in the blood and destroy tumour cells that have specific markers on their cell surface.

Professor Evdokiou has observed that this process is enhanced in the presence of bisphosphonates, a class of drugs widely used to treat cancer-associated bone loss.

If successful, the project will show that this approach is a safe treatment for bone metastasis. As bisphosphonates are already used to treat cancer, this co-treatment strategy could be rapidly implemented in the clinic, leading to significant benefit for patients with advanced disease. .

This project aims to greatly improve the effectiveness of the BreastScreen program, the free government mammography program for women aged 40-70 years. BreastScreen has been successful in reducing the number of Australian women who die from breast cancer by facilitating early detection.

Using the BreastScreen database, Professor John Hopper will compare the screening history and risk factors of women who died from breast cancer with those who died from other causes.

Results will help determine if deaths from breast cancer can be reduced by changing BreastScreen’s screening protocol, taking into account the breast cancer risk factors for individual women. Individualised and evidence-based recommendations could then be made at the time of screening to tailor the screening process for each woman and make it more effective.

This project aims to identify novel biomarkers (molecules that are associated with breast cancer development or progression), which can be used to find breast cancer early. Currently, blood-based biomarkers are used to track disease recurrence or response to treatment, but none is sensitive or specific enough to be used to find breast cancer early.

Professor Douglas Brooks is focusing his research on the endosome-lysosome system, a group of compartments in cells that has a critical role in energy metabolism and cell division. This system, which is sensitive to any changes in the cellular environment, may change early in the cancer process, providing the potential to monitor these changes as an indicator of early breast cancer.

To further explore this theory, Professor Brooks will match components of the endosome-lysosome system with the various stages of breast cancer, to see if an endosome-lysosome ‘signature’ is associated with early stages of the disease.

This project aims to enable the identification of women at highest risk of their breast cancer spreading to other organs in the body (metastasis). There are no effective treatments for metastatic breast cancer.

Only a very small proportion of cells escape the primary cancer and become invasive cells. Professor Alpha Yap is particularly interested in studying these cells and how they break away and infiltrate the lymphatic system and bloodstream. To do this, he will recreate the microenvironment of a breast tumour before metastasis has started.

Understanding the earliest steps in invasive disease, including the events that trigger it, is essential to develop new ways to predict the likelihood of metastasis and treatments to counteract it.

This project aims to increase survival after breast cancer treatment by improving selection of the most effective therapies for each patient.

A high proportion of breast cancers express a protein called BARD1. This protein is unusual in that it is produced in several different forms called ‘splice variants’, which are abundant in breast and ovarian cancers.

Associate Professor Beric Henderson is a world expert on BARD1 function. He has hypothesised that the splice variants of BARD1 may have very different, and even opposing, effects on the way that breast cancers respond to anti-cancer drugs.

In this project, Associate Professor Henderson will clone and express six BARD1 splice variants and examine their effect on how cells respond to radiotherapy and chemotherapy.

With this information, Associate Professor Henderson hopes to define a specific BARD1 ‘signature’ that can be used to predict which patients will respond to chemotherapy and/or radiotherapy.

The next stage of this research should lead to further studies that aim to personalise the treatment of patients based on their BARD1 signature profiles.

This project aims to develop ways to transport chemotherapy more directly to breast cancer cells, avoiding damage to surrounding healthy cells.

Copper, which is important for cell function, enters cells by binding to proteins called copper transporters. The two copper transporters identified in humans, CTR1 and CTR2, also carry platinum into cells. Platinum is the basis for chemotherapies, such as cisplatin, which are commonly used to treat breast cancer. While some patients respond well to cisplatin, others do not benefit from this treatment.

In breast cancers, expression of CTR1 is associated with a good prognostic outcome, whereas CTR2 levels are associated with a poor prognosis. Dr Stuart Fraser’s research aims to identify what cell types in the normal breast express CTR1 and CTR2, and whether the expression of these transporter proteins could help to classify different types and stages of breast cancer.

He will then explore whether breast cancer cells that are not normally sensitive to cisplatin can be made to respond to this treatment by manipulating their levels of CTR using agents called copper chelators.

A greater understanding of the role of copper transporters in breast cancer development and treatment response will help to better tailor treatments to the individual patient – the cornerstone of a personalised approach to cancer treatment.

If successful, this work could lead to the use of CTR as a predictor of response to cisplatin and opportunities to combine chemotherapy with copper chelators to make treatment more effective.

Breast cancer will affect one in eight Australian women and touch the lives of many families. For up to one in 10 of these families, the cancer is due to an inherited gene defect – putting women, and some men, in the family at risk of breast cancer and other cancers, and often at a very young age.

To understand, treat and prevent these cancers, we need to study as many people from these families as possible. kConFab (Kathleen Cuningham Foundation Consortium for research into Familial Breast Cancer) is doing this by collecting unique detailed data and tissues from more than 1500 such families around Australia and making the resource available for research.

Also, the influence of kConFab extends outside of familial breast cancer as it is now clear that studying breast cancers in multiple-case families teaches us a lot about some of the most deadly breast cancers that occur in young women without a family history of breast cancer.

This infrastructure grant will support this world-class resource, enabling research into the molecular causes of these cancers, strategies to prevent breast cancer, new targeted treatments and psychosocial factors that may affect outcomes for these families. .

Early detection and personalised treatment is one of the greatest weapons against breast cancer. Survival and remission rates for breast cancer patients are significantly increased when the disease is caught early.

If the disease is caught at a later stage, the major clinical question is which chemotherapy (if any) should be used to treat the type of breast cancer.

This major new research program hopes to significantly improve breast cancer survival by developing personalised treatments based on the epigenetic code of a patient’s breast tumour.

The research program is a collaboration of Australia’s leaders in genetics, cancer treatment, nanotechnology and pathology, which has already made major discoveries about the genetic markers of breast cancer and has developed new technologies to easily and quickly map those markers.

The new program will take the genetic discoveries and technology out of the lab and into clinical practice, where they will be tested to develop real benefits for breast cancer patients, ie personalised treatment.