Last week, I had the opportunity to speak with students in Freshman Biology classes at Overton High School here in Nashville. I’d given science demonstrations before—including fun with dry ice and a mouse organ scavenger hunt/anatomy lesson that was fun for everyone except one squeamish student. But I’d never spoken in detail about cancer biology and cancer research.
I’ve been saying (read: complaining) for YEARS about how scientists are terrible about speaking with the public. We talk to each other all the time at our institutions and at scientific conferences, but not enough of us reach out to our communities, and that’s a shame. First of all, we as scientists should be advocates for the scientific process and for the progress we’re making. Second, scientists are in a position to combat scammers, pseudoscience, and mis/disinformation by sharing our knowledge. Third, most of us are funded, at least in part, by the federal government. I’m funded by The National Institutes of Health (NIH) through The National Cancer Institute (NCI) – those agencies are funded by federal tax dollars. Since I’m paid by tax dollars, I personally feel an obligation to be able to explain what I do and why it is important to taxpayers in terms they can understand.
So, in my new role as a cancer researcher who has also survived cancer, I’m putting my time and effort where my big fat mouth is and getting out there to be an ambassador and advocate for cancer research! I occurred to me that the slides from my recent presentation for high school students would make a great addition to this blog. It covers how normal cells transform into malignant tumor cells at the molecular level.
The goal of this presentation is to provide a brief overview of how damage to DNA, the genetic code that is used to build proteins (the workhorses of a cell) can lead to uncontrolled cell growth and survival – both hallmarks of cancer. Damage to DNA and failure to properly repair that damage can lead to mutation (change in the code), amplification (more copies of a gene than normal), deletion (loss of DNA and the genes encoded). When changes in DNA occur in genes that regulate cell division, this can contribute to cancer. Uncontrolled cell growth is fundamental to cancer.
To understand how DNA damage leads to cancer, we first have to review what DNA actually does – The Central Dogma of Molecular Biology. I covered this in a previous post, but I’ll go over it again for the (vast majority of) people who don’t spend their days thinking about and doing molecular and cellular biology research. The more frequently you see information, the more likely you’ll be to remember it.
DNA is the blueprint that contains instructions for how to build every protein a cell needs for its normal function. Since, as we’ll see in the next few slides, DNA damage can cause huge problems for cells, DNA is protected in an organelle within the cell called the nucleus. It is only unwound from its double helix structure during (1) DNA replication when the cell makes extra copies before dividing, and (2) when tiny portions, genes, are transcribed (copied) into small units called RNA. RNA gets transported out of the nucleus where the code is translated to make proteins. Each sequence of three base pairs encodes a specific amino acid (building blocks of protein). Take home = DNA to RNA to protein. And DNA damage leads to problems with the proteins they encode.
So what do proteins do? The answer is pretty much everything a cell needs to function. Two specific classes of proteins, those involved in regulation and signaling, are the targets of mutations/amplifications/deletions that can lead to cancer. Regulation involves turning cellular processes, like cell division, on and off. Signaling involves proteins transmitting messages from outside the cell to the inside — including messages that tell the cell when to divide.
DNA can be damaged or altered by internal factors and external factors. Errors occur in replication (copying during cell division), and if they aren’t repaired properly, they can lead to mutations. Other things that can damage DNA include ultraviolet light (sunlight – skin cancer), chemicals (carcinogens) in cigarette smoke, and exposure to radiation. Base mismatches can lead to a change in the code. Single-stranded and double-stranded breaks can lead to amplification or deletion of essential genes in the cell division process. Damage to DNA in genes that encode DNA damage repair proteins are especially harmful, as failed repair leads to more mutations, amplifications, and deletions that accumulate and lead to cancer.
Mutations and DNA damage occur relatively infrequently. Most mutations are silent, meaning that they don’t affect the production or function of the protein the gene encodes, and it takes more than one mutation to transform a cell and make it cancerous.
The types of genes that drive cancer include oncogenes and tumor suppressors. In the cell division process, there are many on/off switches that tell the cell when to divide and when to stop the process of division. Oncogenes, which are amplified (more copies of the gene than normal made after DNA damage) or mutated to be super active, are the “go” signals, like a car’s accelerator. Tumor suppressors, which are deleted (genes are lost after DNA damage) or mutated to be non functional, are the “stop” signals, like a car’s brakes. A combination of amplified/mutated oncogenes plus deleted/mutated tumor suppressors transform a normal cell into a cancer cell that then divides uncontrollably, like a speeding car with the brake lines cut.
On/off switches in the cell cycle, the series of steps that a cell follows to divide and make two cells, have the potential to become oncogenes and tumor suppressors.
This slide shows an example of an oncogene and tumor suppressor in a signaling pathway that contributes to breast cancer. Cyclin-dependent kinases (CDK) are enzymes that tag other proteins with phosphates (P) groups, which serves as a signal for the tagged protein to perform its function. In the case of CDK4/6, its substrate RB (off switch for cell cycles) is tagged with phosphate, which marks it for destruction by the cell. When RB is destroyed, it releases its buddy E2F, freeing it to help the cell make more proteins required for cell division. CDK2/4 function is activated (on switch for cell cycle) by binding to its buddy cyclin D1, and is deactivated by its inhibitor p16. The gene encoding cyclin D1 is commonly amplified (more copies) in breast cancer, and the gene encoding RB is commonly mutated or deleted (gene lost or mutated to make a non functioning protein). Thus, cyclin D1 is an oncogene, and RB is a tumor suppressor.
That’s the overview, but this time I include specific examples. There are many other oncogene drivers and tumor suppressors that contribute to breast cancer and other cancers. I’ll cover some of those in future posts. Hope y’all enjoyed this Science Break! Shout out to Dr. Shannon Youngman and the students from Overton for hosting me and asking some great questions!