Professor Jane Visvader is Joint Head of The Victorian Breast Cancer Research Consortium Laboratory at the Walter and Eliza Hall Institute of Medical Research in Australia. Her lab is interested in how the mammary gland of the breast develops, and what goes wrong in breast cancer.
PhD student Giovanni Valenti interviewed Jane for EuroStemCell in September 2011, at Hydra VII: The European Summer School on Stem Cells and Regenerative Medicine.
How did you come up with the idea that stem cells could be one of the keys for understanding the biology of breast cancer?
The idea was based on examples established in other systems, in particular the blood system, also known as hematopoietic system. In the blood, there is a hierarchy of cells: stem cells produce intermediate or progenitor cells that mature into the different types of blood cells we need (read more in our fact sheet on blood stem cells). I trained in the hematopoietic system, looking for proteins called transcription factors that are involved in maintaining this hierarchy of cells. In fact, a number of transcription factors are important for controlling the differentiation of stem cells and determining cell fate decisions – in other words, controlling which type of specialized cells the stem cells produce. In particular, I was looking at those transcription factors that are involved in leukemia, a common type of blood cancer. When I started to think about cells in the breast, it seemed logical that if a hierarchy of cells existed in the blood, a hierarchy would also apply to normal breast tissue and breast cancer.
In most of your studies you look at mammary stem cells in mice. How many of the findings made in the mouse can be translated into the human?
They are remarkably similar. There are a few anatomical differences between the mouse and the human mammary gland, but the precise cell types that make up these glands seem to be identical across species. Not only have the mammary cells got the same functions in mice and humans, but they also share many characteristics and many genes are turned on (expressed) in both. So I think that the mouse is a fantastic model to help us understand many aspects of human breast cancer.
What could be the implications of your findings for breast cancer therapy?
One of the most exciting paths currently being explored in the lab is the production of xenograft models. That is, we take breast tumours directly isolated from patients and grow them in mice. We have to ‘turn off’ the immune system of the mouse to stop the tumour from being rejected, but we can grow about 20% of human breast tumours in mice in this way. The growing tumours then act as models that we can study, and they can be very helpful for research into new therapies against breast cancer. In particular, we are using these xenograft models to search for genes and proteins that behave differently in normal and cancerous tissues. The aim is to find ways to identify malignant tissues very specifically by looking at the proteins that are present. We can then use the xenograft models to test whether these proteins may also be useful as targets for new anticancer drugs. One example is a protein called c-KIT. We noticed that a lot of c-KIT is made (or ‘expressed’) in certain progenitor cells in the mammary gland, the cells that will mature to build up the gland. Interestingly the expression of c-KIT is increased in many basal-like cancers, one of the most aggressive forms of breast cancer. These tumours are very difficult to treat because there isn’t a way to pick out just the tumour cells and target them with drugs. We are trying to use our xenograft models to test whether a drug that targets c-KIT might be effective for the treatment of basal-like breast cancers.
"Understanding more about the cells that start tumours will eventually help to identify new ways to predict breast cancer and new targets for breast cancer treatments"
What are the big questions in breast cancer research that need to be answered in the near future? And how will your research contribute to finding the answers?
There are still many questions about normal mammary gland development. They will be answered in the mouse first because it is far easier to study than human breast tissue. We need to better identify which are the stem cells in the mammary gland and understand the cellular hierarchy- what cells come immediately after the stem cell in this system? We have begun to understand some of the molecules that are important in controlling this hierarchy, but we need to understand many more. In particular we have to identify those molecules that are important for tumour formation or, on the other hand, can block the growth of a tumour. We need to understand more about which cells are responsible for the origin of human breast tumours. Actually there are at the least five different types of breast cancer and our hypothesis is that they are established by different cell types. We are trying to understand more about the cellular origins of breast tumours by comparing normal breast tissues with different breast tumour types, looking at the differences, a bit like a ‘spot the difference’ game. We have made some important correlations here, but of course we need to prove how things really work in the body now. Understanding more about the cells that start tumours will eventually help to identify new ways to predict breast cancer and new targets for breast cancer treatments.
What are the main obstacles for mammary stem cell research?
There is a lot we can do with the mouse but we are not going to be able to reproduce the human breast precisely. That’s why we need to ‘humanize’ the mouse mammary gland, meaning make it more similar to the human breast. This will allow us to perform studies in the mouse with the advantage that the cells are in a human-like environment. It has proven very difficult to do this effectively despite many efforts. So this is a big challenge. In terms of other obstacles… I think we have to be aware of the fact that when we take cells from breast or mammary tissues, we are disrupting the normal contacts between the cells and also removing them from their surrounding environment. This means the cells will lose many important signals that can affect their properties and functions. It is really important to understand the interactions cells have with their “neighborhood” in order to reproduce them and create artificial conditions that are more similar to the normal conditions in the body
What is the most important finding and exciting moment in your career?
I have been fortunate to have several exciting moments throughout my career, but I think the most exciting moment was when Mark Shackleton and François Vaillant came in with proof that they had generated a mammary gland from a single stem cell. We almost kissed the floor! The research was published in the journal Nature in 2006.
"I considered medicine, but was much more interested in research and trying to understand how things work"
When did you decide to become a scientist?
I think I decided a long time ago, more or less as a student at secondary school. I considered medicine, but was much more interested in research and trying to understand how things work in a biological sense, including how cancer arises.
What have been the fundamental steps in your career?
Many steps have been fundamental to my training along the way. I did my PhD with a fantastic molecular biologist and was then fortunate to work as a post-doc at two different places in the US, the Salk Institute and the Childrens’ Hospital in Boston, where I worked on transcription factors important for hematopoietic development. Both of these experiences were incredible and provided me with invaluable training for my career. Around 1997, I had an opportunity to make a switch to breast cancer – a very exciting challenge, where I could extrapolate principles that I had learnt from the blood system to solid tumours.
What advice would you give someone who wants to pursue a career as a scientist?
You need to be extremely passionate about science and highly motivated. Obviously you also need to be hard working and rigorous and not to expect things to work the first time. As everyone knows, science is full of ups and downs, but the ‘up’ moments really make it worthwhile. They can keep you on a high for months! But it can be a slow process. Therefore, passion, motivation and perseverance are the best ingredients to make a good scientist. Actually, the same applies to all professions if one wants to do well!
Which qualities do you need to become a successful leader of your own research group?
I think you have to be able to interact well with people and to create an interactive environment at all levels – something that’s quite tough to do. My office door is always open as I try to do my best to help with trouble-shooting etc. And of course it’s important to come up with good projects too – something that is equally difficult. One needs to give young scientists a challenging project, plus a less challenging one, so they can sense what it is like to produce results within a year or two. Challenging projects take far longer.
Three things you love about science and three you hate…
One thing I love would be trying to understand the puzzle of how cells and tissues work. Another would be interacting with younger scientists coming through the lab plus the larger community at conferences. It is an incredible profession from that perspective, being able to travel and meet scientists from other parts of the world. You come back with so many ideas from meetings – it is very worthwhile. Things that I don’t like… the grant system. We tend to spend far too much time writing applications for grant money and it can take a lot of time away from thinking and coming up with new scientific strategies.
Find out more
More about Jane Visvader:
Related articles on EuroStemCell:
Information for cancer patients:
- European Cancer Patient Coalition
- Cancer Research UK
- Macmillan Cancer Support
- American Association for Cancer Research
Scientifc papers (Journal subscriptions may be required):
- Generation of a functional mammary gland from a single stem cell, Nature 439, 84-88 (2006); doi:10.1038/nature04372
Image of blood cells by Anne Weston/Wellcome Images. Remaining images by the Jane Visvader laboratory.