The 2012 CTRC-AACR San Antonio Breast Cancer Symposium, 4-8 December
A new oestrogen receptor protein target
Dr Jason Carroll – University of Cambridge, UK
We’ve known for a long time that oestrogen receptor is the driving factor that switches on the genes that cause cells to grow and we assumed the presence of oestrogen receptor meant that oestrogen receptor did the same thing, it went and switched the same genes on, but it turns out that’s not the case. So when we map oestrogen receptor DNA interaction sites in different tumours we find tumours that have a different clinical outcome have different oestrogen receptor genomic contact points. So what we think is happening is that the same protein can go to different regions in the human genome and, depending on the regions in the genome it sits on, it switches on and switches off completely different sets of genes and this ultimately contributes to the outcome of the breast cancer.
Have you been looking at these targets of oestrogen receptors?
We discovered it from analysis of our genomic mapping of oestrogen receptor. So we pulled out every oestrogen receptor DNA interaction site in a breast cancer genome and we kept on finding this DNA sequence and it turned out it pointed us in the direction of a different protein, a protein that we had never even heard of at that time. We pieced together what was going on and it turns out this other protein seems to be a partner of oestrogen receptor and oestrogen receptor absolutely requires this other protein and without it oestrogen receptor doesn’t function. I think the traditional or the established paradigm was that oestrogen receptor on its own was capable of interacting with DNA and switching genes on and it turns out it’s not that simplistic, it requires this partner protein which is called the pioneer factor because it allows the oestrogen receptor to sit on the DNA when oestrogen receptor is unable to do so on its own.
What does this mean for tumour progression?
It looks like this partner protein, it’s called FOXA1, this pioneer factor seems to be critical in driving oestrogen receptor function. So without FOXA1 oestrogen receptor doesn’t work, it doesn’t mediate gene expression. So from our point of view FOXA1 is a vulnerability, if we can block FOXA1 we have a way of stopping tumour progression. So for oestrogen receptor to mediate gene expression that ultimately causes metastasis it requires a protein partner, FOXA1, so we think it’s a potential therapeutic target and it’s something that we are actually trying to make a drug against. We’ve got biological confidence that FOXA1 is the right target, it’s a transcription factor which means it’s not readily accessible by drugs, it’s expressed in the nucleus of a cell. These are traditionally quite difficult to drug and we have just started screening to find inhibitors against FOXA1 so it is early days. We’re pretty comfortable that it is the right target that we need to be trying to drug so what we need to do is start attempting to do exactly that and make small molecule inhibitors that will target FOXA1. Also we know very little about the biology of FOXA1, we don’t know what’s upstream of it so we’re trying to piece together the enzymes and the proteins that regulate the FOXA1 itself. This might be a more manageable way of controlling FOXA1, by targeting an enzyme, a kinase or an enzyme upstream of FOXA1, but at this point in time we don’t know what those regulatory proteins are so we really need to piece together on a nuts and bolts level what it is that regulates FOXA1.
We’re a research based lab so we’re not set up to make drugs. Our job is to try and decipher and delineate the biology and that’s exactly what we do, we pull apart the protein complexes, we identify the targets and we prove that our hypothesis about how the bits fit together is correct. Trying to make drugs, that’s an enterprise and a specialty unto itself so we’ve had to collaborate with people that do that for a living; people that have large libraries of compounds; that have the high throughput equipment to be able to screen these libraries of compounds and have access to the chemists and all the peripheral scientists and the peripheral needs that are required to take small molecules all the way through the process. So we’re definitely not set up to do that and that’s a pretty big investment. We’ve been collaborating with Cancer Research Technology and they are set up to do exactly that. But without the collaborations we wouldn’t be able to do it. As a basic biologist we can only take it so far but if we really, genuinely want to translate our information we need to be tapping into the skill sets and the resources that people like Cancer Research Technology and some of the pharmaceutical companies can provide.
Are you any closer to understanding the problems with resistance?
I think the problem is that there are as many mechanisms for resistance, both to Tamoxifen and to aromatase inhibitors and even pure steroidal anti-oestrogens like fulvestrant. There are multiple mechanisms that a tumour can utilise to overcome the growth arrest mediated by these oestrogen receptor antagonists. So what we’re trying to do is we’re trying to identify commonalities and we have some confidence that there are certain pathways, growth factor pathways particularly, that seem to be up-regulated or altered in endocrine resistance. But these pathways are composed of many, many different steps and sometimes it’s not always the same step. So rather than looking for individual proteins or mutations, I think what we need to be doing is looking for pathways and that is the case. We are starting to identify commonalities in these pathways but there are many, many different ways for a tumour to get around anti-oestrogen mediated growth arrest.
