2010 San Antonio Breast Cancer Symposium, 8-12th December, USA
Interview with Professor Geoff Lindeman (The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia)
Understanding stem cells to get abreast of breast cancer
One of the things that has been a long-held question in the field is how steroid hormones actually regulate breast function and what roles they play in breast cancer. So it’s long been recognised that excess of hormones such as oestrogen and progesterone can increase breast cancer risk, and in fact there’s even a surge in the risk of breast cancer following pregnancy. But the cellular basis for this has been poorly understood.
One of the approaches that we’ve taken is to try to dissect the different cell types in normal breast tissue, in this case using mice. Through our initial discovery of the stem cell and evaluation of the stem cell we’ve discovered that the stem cell is profoundly sensitive to hormone signalling. Now this actually came in one sense as a surprise because the stem cells lack the sensors or the hormone receptors for oestrogen and progesterone signalling so it suggested to us that there are indirect means by which stem cells are being switched on by female hormones. One of the things that Marie-Liesse Asselin-Labat did in the group who performed most of this work was to identify RANK ligand as one of the key signalling factors that switches on stem cells in response to hormones.
How can these discoveries be further used?
Intervening with hormone signalling has played a very important role in the management of breast cancer and also in helping to prevent breast cancer. So, for example, we know that women who have an oophorectomy at the pre-menopausal stage reduce their risks of breast cancer and certain drugs, such as Tamoxifen, switch off signalling and help prevent breast cancer too. Now the problem with these approaches is, of course, that they have collateral damage in terms of potential side effects. By identifying key signalling molecules, such as RANK ligand, we believe that there is a new approach that could be investigated to try to help minimise or reduce breast cancer risk by having a more targeted approach to breast cancer prevention.
Now we’re very excited by the identification of RANK ligand as one of the key players because there are already anti-RANK ligand antibodies that are entering clinical trials and we would speculate on the basis of our findings that these might also, in the long term, find some place in helping to prevent breast cancer.
What are they being trialled for at the moment?
RANK ligand inhibitors are being tested in a number of contexts, one of which is particularly relevant for breast cancer and that is to help minimise the damage to bone from bone metastases for patients who have developed metastatic disease. But also it’s now being tested in clinical trials to see if it could actually prevent metastases to bone happening. So one of the other effects, potentially, could be to actually impede tumour function or even to prevent new breast cancers. Although the studies haven’t been specifically designed to address the prevention aspect, it’s something that might well be worth reviewing in the future.
Are there plans to run trials in the same vein?
Those sorts of prevention studies would require larger numbers of patients. I think the studies that are underway will hopefully provide some insights into this question and maybe inform some proof of principle going forward.
We don’t believe that RANK ligand is the only player, there may be other important stem cell regulators that could also be investigated in this context.
Has the age of pregnancy been taken into account?
There are a lot of hormonal factors which are important as risk factors for breast cancer. Pregnancy and early pregnancy is protective against breast cancer normally; late age it’s potentially thought to increase breast cancer risk or null the parity, never having had children.
What’s interesting also is that breast cancer itself provides a short-term trigger for an increase in the risk of breast cancer. Now our recent findings have discovered that there’s some eleven fold expansion in stem cell number during pregnancy and we would speculate on the basis of these findings that those increased stem cells that arise during pregnancy may account for that short-term increase in the risk of breast cancer that is seen for several years following pregnancy.
Now in the longer term pregnancies provide protection against breast cancer but in the short-term there’s certainly an increase in risk and it could be that stem cells are the culprits.
You also presented an abstract at SABCS 2010?
One of the questions that we’ve been interested in understanding is whether or not certain cell types in the breast are the culprit cells which can give rise to different types of breast cancer. The modern approach to breast cancer has been to perform molecular profiling and to identify different sub-types of cancer and clinicians are now treating patients on the basis of these different sub-types. One of the views that had been held in the field is that the stem cell was the key cell which gives rise to a particularly aggressive form of breast cancer known as Basal-like breast cancer. These account for about 20% of all breast cancers and are by far the most lethal.
So the findings that we have made suggest that it’s actually the daughter of the stem cell, the cell known as the luminal progenitor cell, which is perhaps more likely to be the culprit cell which gives rise to Basal-like tumours. The basis for this finding really was to look at tissue from BRCA1 mutation carriers. These are women who have a very strong predisposition for developing breast cancer and what we found was that there was in fact an expansion of the luminal progenitor population in BRCA1 women. In fact, if anything, there was a decrease in the stem cell numbers in pre-malignant breast tissue taken from BRCA1 women. This certainly points the spotlight on the luminal progenitor cells being a potential target cell.
We also found that luminal progenitor cells misbehave in terms of their growth properties when grown in the laboratory in certain assays so that the luminal progenitor cells from BRCA1 patients developed factor independent growth even when taken from normal patients undergoing prophylactic mastectomies. So this certainly suggests that these cells are the key target cells which might give rise to BRCA1 tumours.
How do we target the luminal progenitor cell?
Now that we have identified the luminal progenitor cell as being a cell of interest, we’ve actually performed gene profiling of the different sub-types of epithelial tissues in human and, in fact, in mouse breasts and looked for key signatures of the different sub-types. By searching through signature genes of the luminal progenitor cell, for example, we now have some potential targets that can be investigated to see if they can alter the behaviour of the luminal progenitor cell and then in turn see if these have some relevance to Basal-like breast cancer.