Welcome back to An Introduction to Breast Cancer. I'm Dr. Anees Chagpar. I'm so glad you chose to join us today. Over the last few sessions, we've talked a lot about breast cancer. We've talked about the epidemiology of breast cancer, risk factors, what we can do to prevent it. We've even talked about types of breast cancer. But fundamentally, what causes breast cancer? Why do people get this, anyways? What causes these cells to somehow go awry? That's what we're going to talk about today. So remember back to our very first session? We met up with Calvin and Hobbes, and we went to the dictionary to find out what is cancer? And we discovered that this was a disease caused by the uncontrolled division of abnormal cells in a part of the body. The two key words were uncontrolled division and abnormal cells. But why does that happen? What happens to that regulatory control that all of us are built with that prevents our cells from becoming abnormal, and prevents them from running amok? Well, there are a number of key factors that go into regulating that process. And when those factors are disregulated, then we have the hallmarks of cancer. Let's look at some of those. This is a very nice paradigm for thinking about cancer and different mechanisms that may be at play when we think about what disregulates cells and causes them to become cancerous. As we go through them, you can think about how these factors interplay, so that we get uncontrolled growth with disregulation, getting an accelerator pedal without a brake pedal. And really causing our body to let these cells run amok, without the regulation that we normally have. Let's start at the top. So sustaining proliferative signaling. This is essentially keeping that accelerator pedal on without any brake pedal. Evading growth suppressors. So that is hiding behind a little cloak, preventing your body, that normally would stop uncontrolled growth, from running awry. So with this, when you evade these growth suppressors, you continue to have that accelerator pedal, without a brake pedal. You avoid immune destruction. So your body has an immune system that is highly specialized to prevent you from getting infections, but also to prevent you from getting any abnormal activity. When these cancers can hide behind an invisible cloak, the immune system has no way of detecting them. And so this is actually an area that has been one of very active research with immunotherapies. We might talk about that a little later on. You enable replicative immortality, allowing cells to continue to replicate, grow forever. And tumors can promote inflammation. So with that inflammation, you promote more tumor growth. Well, again, this is keeping that accelerator pedal on. In the last session, we talked about invasive cancers, and how critical it was for these invasive cancers to invade that basement membrane, giving them access to blood vessels and lymph vessels so that these cancer cells could spread all over your body. Well, when you activate that invasion and you activate metastasis, it's a recipe for cancer to spread. In order for those cancers to spread, they need a pathway, a portal, often blood vessels. So cancer cells can induce angiogenesis. Angiogenesis is building of new blood vessels. The more blood vessels the tumor can build around it, the better access it has to the rest of your body. And we talked about genes that could be turned on that could allow these cancer cells to turn into cancer cells, as opposed to staying as normal cells. They resist cell death, which is normal, programmed cell death, because all of our cells, as they grow and divide, need to stop dividing at some point. They need to die. Cancer cells say, no way, I'm going to live forever. And so they do. They resist cell death. And so again, they're losing that brake pedal, only keeping the accelerator. And they deregulate cellular energetics. They use their energy to promote their own growth. So you can see how all of these very fancy pathways essentially boil down to the same fundamental concept. Keeping an accelerator pedal without any brake pedal, having massive growth of abnormal cells without any rules, without any regulation. And knowing about all of these pathways is really critical, because it helps us to think about what could we do as we design new therapeutics that can attack these mechanisms. Ultimately, we want to stop cancer cells from doing all of these things, so that we gain back control. Now let's look at a very simple model. I'm going to give you a caveat here. This is very simplified, but I show it to you so that you kind of get an idea of progression of disease. The last time we talked about cancer, and we talked about in situ cancers, pre-invasive disease, and we talked about invasive cancers, those that have access to blood vessels and lymph vessels, and the ability to spread. If we go back and we look at a linear multi-step model, you can imagine that normal cells can gain some proliferative changes, that is to say cells can grow. They're still very controlled. They're still not abnormal. They're just growing, which is fine. At some point, they begin to become atypical, funny-looking cells. Remember back to our lecture on risk? We talked about the nine proliferative changes, like atypical ductal hyperplasia, increasing your risk for developing breast cancer. In and of itself, it's not premalignant. It doesn't turn into a cancer. But it does increase risk, and it can hang out with pre-cancers and cancers in the same vicinity. Then, as you acquire more changes and the cells get more bizarre, you can get ductal carcinomas in situ. Again, these are abnormal cells. They are premalignant cells. But here, they're confined by that basement membrane, so they don't have the ability to spread. Once those pre-cancer cells corrode through the basement membrane, now they become invasive and they have the ability to spread. So how do these changes occur? Well, it's really an accumulation of genetic and epigenetic changes. So initially, it might just be an abnormal response to growth factors, things like estrogen receptor. And we talked a lot about estrogen when we talked about risk and prevention. Failure to respond to normal cell death signals or apoptotic signals. And then, as some of the tumor suppressor functions, those are genes that we have that prevent us from getting cancer, get lost, so things like p53, we start acquiring more mutations, and we start being able to form more tumors. So between a loss of tumor suppressor genes and an acquisition of oncogenes like HER-2, cancer cells can start to form along with genetic instabilities, so not being able to control how these genes are expressed. All of a sudden, you end up with ductal carcinoma in situ or pre-invasive cancers, which, as soon as you start getting tissue invasion by malignant cells, and stromal changes with angiogenesis, building of blood vessels, all of a sudden, now you come up with a clinical phenotype of invasive cancer. So in a nutshell, as you acquire all of these changes, that's how cancer progresses and how we get to truly invasive cancer cells. It's not just one thing. So when, oftentimes, patients say well, what caused my cancer? How come there isn't one thing that we could just turn off? It doesn't seem to be quite so simple. Let's look at atypical ductal hyperplasia. I want to draw particular attention to this step, because I think that it can be confusing for a lot of people. It is not, clearly, totally benign, like benign proliferative changes, because it's atypical. It has funny-looking cells. But on the other hand, while it increases risk, it's not pre-invasive. It's not like an in-situ cancer, that if left there long enough, would corrode through the basement membrane and become an invasive cancer. So what is atypical ductal hyperplasia? It's really a marker of increased risk that is defined by these atypical cells. What's important about atypical ductal hyperplasia is that when you have a core needle biopsy, so that is to say a biopsy that's done with a needle not bigger than my pen, and you find atypical cells, oftentimes we'll need to take out that area, not because this is a cancer, but because in 14 to 17% of cases, these funny-looking cells can hang out with even funnier-looking cells that are in situ or invasive cancers. In and of itself, however, atypical ductal hyperplasia is simply a marker of increased risk, like we talked about in the risk lecture. And for the most part, selective estrogen receptor modulators like tamoxifen are very effective in reducing the risk associated with atypical ductal hyperplasia. Now, we've talked a lot about cancer and breast cancer, who gets it, why they get it, how we can prevent it, what causes it. What I hope to do over the subsequent lectures is talk about what we can do about it. I want to give you one patient anecdote. This is a quote from one of our patients who wrote a blog, and I encourage you to check it out. The link is here. She says cancers can go to beep because she decided that she was going to be fine. She was going to run this show, not a bunch of mutant cells. So we know that cancer is a bunch of mutant cells, abnormal cells growing in an uncontrolled way. Over the next subsequent lectures, what we hope to talk about is what we can do about this, how we can control cancer so that cancer doesn't control us. I hope you'll join me. Until next time, I'm Dr. Anees Chagpar.