Scientists are only two years from developing a cure for breast cancer?

Want to know what will start my teeth grinding when I read it in a newspaper? That's easy. It's headlines like this one, which appeared two days ago in The Telegraph:

Scientists two years from developing 'potential cure' for breast cancer

The subtitle was even worse:

British scientists could be just two years away from developing a drug that may be a "potential cure" for breast cancer, it has been claimed.

Hear that grating? It's the sound of my teeth grinding together. The reason is simple. It's just plain silly to make claims like this about a basic science paper given that, as I have discussed before, it often takes decades for basic science observations to wend their way through that long strange trip to becoming actual therapies used by clinicians. The life cycle of translational research is long, and efforts to speed it up have only met with mixed success:

Researchers have found that the cancer manipulates molecules, called microRNAs, to allow malignant cells to spread throughout the rest of the body.

The discovery means they can now work on developing a drug to stop this process.
Dr Justin Stebbing, senior lecturer and consultant medical oncologist at London's Imperial College, is one of the experts behind the breakthrough.

"There are no available drugs as yet but they should be available within a couple of years. This is a potential cure for breast cancer," he told the Daily Express.

"This is a step on the way to it and it helps us understand the way breast cancer cells grow and divide and if we understand this then we understand how it stop it."

With all due respect to Dr. Stebbing, no and yes. No, this is highly unlikely to be a "cure" for breast cancer, any more than immunotherapy was in the 1980s, Herceptin was in the 1990s, antiangiogenic therapy was in the 2000s, or any of a number of touted "cures" that have cropped up over the years. It does not become a cancer scientist to make such statements. On the other hand, yes, this is interesting basic research that could well lead to new therapies for breast cancer in several years. But it's not a cure; it's not likely to lead to a cure quickly; and it really irritates the crap out of me to hear Dr. Stebbing claim that something like this is likely to lead to a cure that fast. Yet this claim has been reported under headlines like the one above and these:

• Breast cancer breakthrough
• Scientists 'close to breast cancer cure' after British researchers find a way to stop tumours growing

Would it were all true!

So what is the study whose promise is being so hugely exaggerated? It appeared in PNAS¹ and represents a report of the work of Dr. Stebbing's group in concert with Gregory J. Hannon's group at Cold Spring Harbor and involves a kind of regulatory molecule known as microRNAs. It helps that Dr. Hannon is one of the founding fathers of RNA interference and gene silencing, although he didn't win the Nobel Prize for the discovery, as Professor Andrew Z. Fire at Stanford University, California, USA, and Professor Craig C. Mello at the University of Massachusetts Medical School did in 2006. This represented the shortest period of time from initial publication of a discovery and the winning of a Nobel Prize for it. RNA interferences (RNAi) was only discovered in 1998, and it's the first time I can remember of a Nobel Prize being awarded for something that was discovered since I've been in science. Even better, it was awarded for something that I've become interested in, because over the last few years I've become very interested in RNAi, and, in particular, the short RNA sequences that mediate it.

In particular, I'm interested in one specific RNAi mechanism, that mediated by specific short sequences of RNA that are not transcribed into protein known as microRNAs. That's what this paper is all about. MicroRNAs in general result from the processing of larger precursor RNAs that are cleaved to 21-23 nucleotide stretches that have a complementary sequence to specific messenger RNAs (mRNAs) responsible for coding for protein. What happens is that a microRNA binds to the complementary sequence in a mRNA and then either induces the degradation of that RNA or inhibits the translation of that RNA into protein. Either way, the end result is the same: The level of the protein that the mRNA targeted by the microRNA codes for decreases. In other words, microRNAs shut down gene expression, and they do it very specifically. Indeed, over the last few years, it's become more and more appreciated that microRNAs are a very important post-transcriptional (after the mRNA is made from DNA) regulatory mechanism for controlling gene expression, or how much protein a given gene makes. Because microRNAs are so specific, it is not difficult to imagine trying to target genes using them to shut down a gene quite specifically, and, indeed, that's exactly one area that scientists are studying. In addition, it turns out that microRNAs represent a very important regulatory mechanism controlling key molecules and that alterations in what microRNAs are or aren't made can have a profound effect on the transformation of normal cells into malignant cells. They target multiple important cancer-related genes, and in some cases they are more accurate a predictor of tumor type than the genes they regulate.

What Dr. Stebbing looked at was the role of microRNAs in regulating the expression of the estrogen receptor, which is incredibly important in breast cancer. Basically, the estrogen receptor (ER) is a protein in the cell that estrogen binds to. After estrogen binds to it, the estrogen receptor moves into the nucleus and turns on various genes that cause the cell to grow, among other things. The reason ER is so important in breast cancer is because over 2/3 of breast cancers are what we call estrogen receptor-positive (ER+), meaning that they make the estrogen receptor and are therefore stimulated to grow by estrogen. That's why the mainstay of breast cancer therapy, at least for ER(+) cancers, is antiestrogen therapy such as Tamoxifen or aromatase inhibitors. Unfortunately, only approximately 70% of ER(+) cancers respond to antiestrogen therapy. Worse, even those that do respond frequently become resistant to antiestrogen drugs. Antiestrogen resistance is a very serious problem in breast cancer; when breast cancers become resistant to Tamoxifen usually all that's left is chemotherapy.

Stebbing observed that the activation of the ER results in the production of specific microRNAs that in turn target the mRNA for ER. Thus, the activation of the ER results in a feedback mechanism that attenuates and shuts down the cell's ability to respond to estrogen, thus terminating the response before it can get out of control. In breast cancer, under estrogenic stimulus, an oncogene known as c-myc is activated, and c-myc in turn activates specific microRNAs. The interesting result of this study, at least as described by the authors, is that in ER(+) cells, for some reason the normal precursors of these microRNAs that target the ER are not properly processed into active microRNAs. In other words, for some reason the feedback loop that shuts down ER signaling doesn't get turned on as it normally is, leading to continued stimulation.

These are all interesting results, but there are a number of problems and challenges that make any proclamation of a "cure" within two years to be premature at best and irresponsible at worst. First of all, the in vitro work was all done in a single cell line, MCF-7 cells, a breast cancer cell line isolated from cells in a pleural effusion of a woman who died of breast cancer back in the 1970s. Every experiment looks at either MCF-7 cells or MCF-7 cells that are genetically modified to do various things. There's no way of knowing if Stebbing's result is generalizable to most, many, or even a few ER(+) breast cancers in humans. In addition, there was no direct comparison of the levels of the two precursor microRNAs that correlated with ER levels between normal breast tissue and breast cancer, an important omission. True, the investigators did measure levels of the two microRNA precursors in a small number of human breast cancer specimens and found that they correlated with ER mRNA levels, but that's more correlative and supportive, rather than particularly convincing. They also noted in many more samples that one of these same two microRNA precursors is expressed at a higher level in ER(-) breast cancer cells than in ER(+) cells, but, even though the result is statistically significant, I wonder how biologically significant it is, given that the difference is small and there is considerable overlap. I also wonder why the used so few samples to look at whether these microRNA precursors correlate with ER levels in ER(+) breast cancer when they clearly had many more ER(+) breast tumors that they could have looked at. Finally, in all of the cell culture, there were in essence no functional data presented, in other words, data that show that manipulating these microRNAs have biological effects at the cellular level that would indicated that, for example, increasing their level would shut down breast cancer cell proliferation or metastasis, and there was no animal data that suggested that the microRNAs described were functional in tumors.

As I said, this was a strong preliminary study, but it lacked functional data and animal studies.

Worse, the investigators go far beyond what their study shows when they speak to the press:

Scientists have previously focused on how to prevent tumours from forming, but the new research has found key molecules called microRNAs which the cancer manipulates to spread around the body.

Breast cancer cells 'switch off' these molecules, allowing the cancer to spread unchecked to other parts of the body.

This spread is responsible for 90 per cent of deaths from breast cancer and the team which made the breakthrough is working on a drug to stop this fatal process.

There was nothing--I repeat, nothing--in Stebbing's study that looked at whether these two precursor microRNAs and the mciroRNAs that derive from them affect metastasis. The above statement is ridiculously overblown and completely unjustified based on the content of the paper. I hate it when scientists feed the press conclusions based on the data from their papers that reviewers would never have let them get away with in the actual manuscript. (Here's a hint: "complementary and alternative medicine" practitioners do this all the time.) Stebbing would l do well to learn from the example of one of my scientific heros, Judah Folkman. Back in 1998, when he produced evidence far more compelling than anything in Dr. Stebbing's PNAS article that he had found a highly effective treatment for cancer (after all, he had animal data; Stebbins does not), Dr. Folkman did not say things like, "This will lead to a potential cure for breast cancer in two years." Dr. Folkman appreciated how difficult it is to translate basic science into actual clinical therapies. Stebbins would do well to remember a famous quote from Dr. Folkman, variants of which I personally heard him say in two different talks and which was described in this excerpt from a People article on him in 1998

Now, Folkman, 65, a researcher at Children's Hospital in Boston, has offered hope to the world. Though he hastily counseled caution as news spread that his pioneering work with lab animals could lead to a breakthrough in curing cancer--"If you have cancer and you're a mouse, we can take good care of you," he said--the excitement of the moment was palpable.

Dr. Folkman knew that scientists had seemingly cured various cancers in mice many times before but that those results were generally not as dramatic in humans--if they even translated into human results at all. Consistent with Dr. Folkman's caution, eleven years later antiangiogenic therapy has taken its place in our armamentarium of cancer therapies, but it is most definitely not a cure.

The bottom line is that Stebbing's work is good science that was badly reported. It's preliminary and basic at its core, which I like. It's also nice, hardcore molecular biology and provides some tantalizing observations that might suggest a molecular pathway that could well be targeted to treat breast cancer. What it does not do is to provide a pathway to target that is likely to result in a cure for breast cancer in two years. I really wish it did, but it doesn't. Maybe in a decade or so, this work might result in a usable drug targeting this pathway, somewhat sooner if everything goes very well indeed. Dr. Stebbins would do well to contemplate the example of Judah Folkman before talking to the press again. The hyperbole used to describe this microRNA research soured my enthusiasm for Stebbing's work. Indeed, I smell a pitch for money for a startup company to develop a therapy based on this work.

REFERENCES:

1. Castellano, L., Giamas, G., Jacob, J., Coombes, R., Lucchesi, W., Thiruchelvam, P., Barton, G., Jiao, L., Wait, R., Waxman, J., Hannon, G., & Stebbing, J. (2009). The estrogen receptor- -induced microRNA signature regulates itself and its transcriptional response Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0906947106