LB 145 Cancer Unit

Mammary Glands

-All humans, regardless of gender have mammary glands (w/ the exception of those who have had a mastectomy) -Composed of adipose tissue + lobules + ducts. hormones like estrogen and prolactin play key roles when it comes to the capacity of. these glands to express milk

The TP53 gene is located on chromosome ___________. It has __________ nucleotides which code for a protein that is _______ amino acids long.

-chromosome 17 -about 2600 nucleotides -393 amino acids

4 Key Features of Evolutionary Medicine

1. It is integrative 2. It is focused on humans 3. It is comparative 4. It has implications for how we understand and treat human health

Let's say that Dr. White quits his job and opens an elephant zoo. His favorite elephant is named Zeus. As time passes, Zeus develops a tumor on his leg. This doesn't seem right? Elephants are supposed to be immune to cancer? Dr. White decides to get Zeus genetically tested and discovers that 14 out of 20 of his TP53 genes have nonsense mutations in them. 1. How would the presence of these mutations impact Zeus's susceptibility to cancer? 2. Are there any other genetic reasons that could be responsible for Zeus's tumor? 3. Are there any non-genetic factors that could contribute to the development of Zeus's tumor?

1. The tumor suppressor genes that have picked up mutations will be less effective or ineffective at repairing damaged DNA or initiating apoptosis, leading to a much higher risk of cancer. 2. Mutation in a proto-oncogene could also increase his risk of cancer. 3. Environmental conditions, carcinogens, diet, etc.

Why would a cell ever self-destruct?

1. some mutations might be detrimental 2. cell may have limited functionality therefore, it is more advantageous to break down cell and redistribute its parts to neighboring cells.

HER2 gene is __________ nucleotides long and it codes for a string of _________ amino acids.

4,000 nucleotides, 1,255 amino acids

G0 phase

A non dividing state in which a cell has left the cell cycle. The cell remains in a state of work and stability for an extended period of time

Antagonistic Pleiotropy

A type of trade-off where there's a positive thing that's offset by a negative thing.

Mitosis

After interphase, the cell enters this process where it replicates itself. It is composed of prophase, metaphase, anaphase, telophase/cytokinesis

Trade-offs

An evolutionary trade-off refers to a situation in which evolution cannot optimize the fitness associated with a specific trait without compromising the fitness associated with another.​ ​ Examples: ​ Organisms that have a lot of offspring may tend to live shorter lives​ Organisms that are larger may tend to have less endurance

HER2 is a transmembrane protein. It is activated by...

Another protein called the epidermal growth factor. When it is activated, it sets off a series of chain reactions that results in DNA replication followed by mitosis. So, a change to the amino acid composition of the HER2 protein might result in an increase in its efficiency, leading it to call for more frequent cell division.

Evolutionary Medicine

Applies modern evolutionary theory to our understanding of human health and disease. Not only can we learn about how the biological mechanisms underlie human health work, but why certain diseases and disorders exist in the first place

Evolutionary medicine has implications for how we understand and treat human health. This means...

At many institutions, evolutionary medicine is treated as a niche specialized field, rather than a core component of health science curriculum. However, one reason biological mechanisms dysfunction and cause harm in the first place is because most modern humans live in vastly different environmental conditions than that of ancestral humans. For example: -modern diets are much higher in sugar -many of us are frequently exposed to harmful chemicals such as those from cigarette smoke

How might non-functional BRCA proteins lead to an increased risk of cancer?

At the G2 checkpoint, BRCA proteins repair damaged DNA or initiate apoptosis. A non-functional BRCA protein would not be able to do so, and this could cause a cell with damaged DNA to continue progressing through the cell cycle. Similarly, BRCA proteins act at the M checkpoint during metaphase to make sure chromosomes line up properly. If the BRCA proteins were non-functional, then it could lead to chromosomal level mutations in anaphase.

How might a non-functional p53 protein lead to an increased risk of cancer?

At the G2 checkpoint, p53 proteins repair damaged DNA or initiate apoptosis. If the protein was non-functional, damaged DNA would be able to progress through the cell cycle. This would in turn lead to an increased cancer risk.

Malignant Tumor

Can damage the organ where it forms and has the potential to become metastatic

Antagonistic Pleiotropy in breast cancer

Can explain why cancer persists in human populations. Studies have found that cis-gender women in families with a documented BRCA1 and BRCA2 variant allele tended to have more children than women from families without this variant allele.

In Situ Cancer (tumor)

Cancer that has remained within the tissue in which it originated. At this stage, the tumor may need treatment if it's malignant.

Multi-Level Analysis of a Fever

Causation: immune response Development: natural immunity Functional: protection from pathogen Phylogeny: all animals have a fever response

Explain how biological conditions act like a checkpoint.

Cell does a "self-assessment" Looks at factors such as: -Does the cell posses enough resources to support two progeny cells? -Is it big enough to divide into two reasonably sized cells? -Are external environmental conditions favorable for cell division?

G2 checkpoint

Cell does another self assessment, checks for cell size and DNA replication.

Cytokinesis

Cell starts to pinch in the middle and results in two new progeny cells.

Four overarching aspects associated with the process of evolution are: (i) the potential for individuals of species to increase in number; (ii) heritable genetic variation; (iii) competition; (iv) "survival of the fittest" Use these ideas to explain how cancerous cells can evolve within a population of seemingly "normal" cells.

Cells are tiny living organisms that are alive. They increase in number and are differentiated between cells of different locations, ex. pancreas cells and voice box cells. They have heritable genetic variation and they compete for resources. Therefore, since cancer cells divide rapidly and pass their genetic info onto daughter cells, they can outcompete normal cells and evolve within the population.

Interphase

Cells generally exist in this period. It has a few distinct phases within it. G0 phase G1 phase S phase G2 phase

Prophase

Centrosome replicates itself and the two centrosome copies move to either side of the nucleus. The membrane of the nucleus is broken down. The DNA in the form of these X-shaped chromatids, they begin to congregate at the middle of the cell. Microtubules begin to form from the centrosomes and start to build towards the middle of the cell.

Cancer is often the result of copying errors that occur during mitosis. In which of the following processes would these copying errors be occurring? A. DNA replication B. Transcription C. Translation

DNA replication. Copying errors that occur in DNA replication would be present in each subsequent transcription and translation, affecting all protein products produced from that DNA.

Double strand break

Damage that results in breaks in both complementary strands of DNA.

Hyperplasia

Essentially just an increase in the amount of cells for a given tissue type. hard to detect, do not always progress into cancer.

Why the 99del5 mutation?

Founder effect. Somebody with this mutation settled in the Scandinavian region of northwest Europe. That person passed on that mutation to their offspring. As that offspring reproduce, more people inherited the mutation. In cis-gender women, this mutation puts them at ~40% increased risk of developing breast cancer. Cisgender men also have increased risk as well.

Phylogeny (evolutionary)

How did evolutionary processes over many generations result in the evolution of the characteristic?

Adaptive (functional)

How does the characteristic influence the individual's ability to survive and reproduce?

What proteins are at play in the G2 checkpoint?

If DNA replication was not accurate enough, p53 can attempt to initiate DNA repair. If that DNA repair isn't possible or isn't successful, p53 can initiate apoptosis. BRCA1 and BRCA2 also play a role in DNA repair.

Zeus has fathered 7 elephant calves. Describe the state of the TP53 gene in Zeus's seven beautiful elephant children. In what circumstances would they inherit "bad copies" of the TP53 gene, and in what circumstances would they inherit only "good copies" of the TP53 gene?

If Zeus was born with 14 bad copies of the gene, he would pass those bad copies onto his children. If Zeus was not born with these copies, but rather picked up these mutations throughout his life, he would not pass the bad copies onto his children. In this case, they would only inherit good copies of the gene.

S phase

If certain biological conditions are present, the cell will move from the G1 phase into the synthesis phase, where the portion of interphase during which DNA is replicated.

Why are cancerous alleles maintained in human populations?

If somebody gets cancer, then it could, on average, reduce their reproductive output. Even if the cancer hits after reproductive time in life is over, it would still be an incredibly difficult thing to go through, and since cancer is sometimes fatal, families that are genetically predisposed to the disease would have less kin support and this would likely result in a lower overall reproductive fitness. So given this, cancer should be selected against? However, antagonistic pleiotropy provides a better explanation as to WHY cancer would be selected for as opposed to against.

Describe the association between HER2 variants and cancer rates.

In around 30% of breast cancers, there is an overabundance of the HER2 protein. If there is an overabundance of this protein, it means that the HER2 gene was likely over expressed -> turned into a protein far more often than it should. This could happen when there is a mutation in the promoter sequence which could result in more frequent transcription.

The most common type of breast cancer is called ______________.

Invasive ductal carcinoma, where a tumor forms among the duct epithelial cells

Evolutionary medicine is focused on humans. This means..

It helps us learn about the relevance of biological evolution in the human species by focusing on research questions that involve human health

Evolutionary medicine is integrative. This means...

It involves the integration of all sub-disciplines of biology, such as genetics, cell biology, evolution etc.

Once a cell passes the G1 checkpoint...

It is irreversibly committed to cell division. If something goes wrong during cell division, there's no turning back, it's either divide or die.

What happens if a cell with errors passes the G2 checkpoint?

It might lead to exponential growth of mutant cells that could become cancerous.

Breast Anatomy

Made of 3 different types of tissues 1. adipose tissue- fat 2. lobules- capable of producing milk 3. ducts- capable of carrying milk from the lobules to the nipple

Milk Ducts

Made up of epithelial cells, which are the same cell types found in skin, as well as the lining of most organs

Cancer and trade-offs

Many aspects of a multi-cellular organism's fitness relies on cell movement and proliferation (e.g. the ability to grow and repair tissue)​ ​ Since these processes require cell proliferation, they can be limited by cancer suppressing mechanisms that have evolved to restrict proliferation​ ​ Therefore, organisms need to balance the benefits associated with the ability to grow and repair tissue with the cost of being more vulnerable to cancer (i.e. a trade-off!)

Most breast cancers involve the __________.

Milk ducts

Multicellular Equilibrium

Mitosis = Apoptosis

BRCA2 Gene

Nearly 85% of the over 2,500 variants are pathogenic. In one example, the 99del5 mutation consists of a deletion of 5 nucleotides at position 999. This leads to a missense frameshift mutation which has a huge impact on the protein product.

Telophase

New nuclei start to form in either half of the replicating cell.

Dysplasia

Next level of growth following hyperplasia, if it continues to grow it can turn into what's called an in situ cancer, also known as a tumor.

Does having a mutated BRCA gene mean you are destined to get breast cancer?

No, but it does increase your risk.

When a person reaches the age of 60, the DNA within most of the cells in their body have accumulated MANY mutations. Although cancer is certainly more common among people in their 60s, why isn't everyone at that age suffering from cancer, given all the mutations within their cells?

Not all mutations lead to cancer, it depends on where the mutation is and if it leads to an increase in cell division or a decrease in the effectiveness of tumor suppressor proteins to repair damage or initiate apoptosis.

Benign Tumor

Not considered cancer, it can't spread to other parts of the body and generally does not harm the organ where it forms

What are some measures to prevent breast cancer and be proactive?

One surefire way to ensure you don't get breast cancer is a double mastectomy. However, preventative measures like regular breast exams and mammograms can also be invaluable for early detection should a cancer start to form.

Cells that replicate into cancerous masses are often able to pass the G1 checkpoint, when really they shouldn't. What would cause a cell to replicate before its time?

One thing linked to cancerous growth is an overabundance of a transmembrane protein called HER2. The HER2 protein will bind to another protein called the epidermal growth factor and then set off a series of chain reactions that helps to pass the G1 checkpoint.

Black and yellow coloration in poison dart frogs How does the trait work? Proximate Why does the trait exist? Ultimate

Proximate: Has alleles to be black and yellow. Therefore, frogs express these colors. Ultimate: Sends a message to predators to stay away. Prevents poison dart frogs from being eaten and predators from eating poisonous species

Crying in human babies How does the trait work? Proximate Why does the trait exist? Ultimate

Proximate: It is an instinctive trait. Ultimate: Allow babies to communicate with caretakers.

Cancer in humans How does the trait work? Proximate Why does the trait exist? Ultimate

Proximate: Mitosis occurs rapidly or apoptosis does not occur frequently enough. Ultimate: Rapid cell division is important for growth and wound repair.

Zoobiguity

Refers to the idea that from a biological perspective, all species on Earth share more similarities than they do differences

Explain Angelina Jolie's well publicized decision regarding breast cancer.

She elected to have a preventative double mastectomy. She has a mutated BRCA gene as well as a family history of breast cancer and these two factors increased her lifetime risk of developing breast cancer.

Knowing why breast tissue is particularly susceptible to cancer, propose other tissues in the human body that might be particularly susceptible to cancer, and which tissues would be less susceptible.

Some tissues in the human body that might be particularly susceptible to cancer are skin cells and cells lining the organs. These cells, like duct cells, are epithelial cells which generate quickly Some tissues in the human body that might be less susceptible to cancer are nerve cells and muscle fibers, which generate less frequently.

M-checkpoint

The BRCA proteins act during metaphase to make sure that the chromosomes are lining up properly. If the chromosomes don't line up properly, then it could lead to chromosomal level mutations in anaphase.

BRCA1 and BRCA2

The abbreviation comes from the BR of breast and the CA of cancer. Mutations in these genes can increase the lifetime risk of somebody developing breast cancer. They are tumor suppressor genes.

Why are duct cells so prone to cancer?

The cells that reproduce at the ducts reproduce at a high rate and on a regular basis. essentially, they reproduce whenever they receive hormone-based chemical signals as part of the normal menstrual cycle Anytime a group of cells has a high reproduction rate it makes them more prone to cancer because anytime mitosis occurs, you have dna replication occurring which opens up the possibility of more mutations happening that could result in accelerated cell division

Ultimate Explanation

The evolutionary explanation of a trait or condition (adaptive function, phylogenetic history, etc.) explains: why does this mechanism exist?

Proximate Explanation

The mechanisms underlying a trait or condition (physiology, hormones, genes, development, etc.) explains: how does this mechanism function?

Metaphase

The microtubules that stretch out from the centrosomes attach to the chromosomes that are now lining up along the middle of the cell.

Why is apoptosis an important defense mechanism against the development of cancer?

The process of apoptosis helps regulate cell division and can inhibit rapid cell division seen in cancer. this can be done by having rapidly dividing cells with mutations self-destruct to protect the individual.

G2 phase

The second growth phase of the cell cycle, consisting of the portion of interphase after DNA synthesis occurs.

Metastatisis

The spread of cancer cells beyond their original site

How are genetic mutations associated with cancer?

There its no such thing as a cancer gene, instead there are certain variants, or alleles of genes that might be associated with greater risk of cancer. These variants can be inherited from a parent or be the result of mutations.

How do mutant proteins actually cause cancerous growth?

To better understand the cell biology of breast cancer, we need to talk about the cell cycle. A cell goes through a series of phases. Broadly speaking, a cell can be in one of two states, either in interphase or going through mitosis. If we understand why a cell would move from a period of stability in interphase to a period of growth and division, then we can understand more about why cancerous growths would occur.

From an evolutionary perspective, what is a "conserved trait"? Identify a few traits that are conserved in humans.

Traits that were selected for and have remained relatively unchanged over time. Some examples include -Crying in babies -Ability to digest milk after infancy. Most species cease production of the lactase enzyme after infancy, but we do not. -Disease resistance against malaria and other harmful diseases in some populations.

Somatic evolution vs organismal evolution

Understanding the evolution of cancer requires two perspectives: the level of the cell (somatic) and the level of the organism​ ​ What is the difference between somatic and organismal evolution?​ ​ In what types of cells do mutations need to happen in to influence each evolutionary process?

Evolutionary medicine is comparative. This means...

We can compare features among species to help us learn important aspects of our own health

Causation (mechanism)

What biological mechanisms are responsible for the characteristic? Ex. hormones, neurotransmitters, etc.

Development (ontogeny)

What environmental factors that influence development are responsible for the characteristic?

Anaphase

Where motor proteins pull on the microtubules and pull the replicated chromosomes in half at their middle attachment point.

Most mutations in coding regions typically reduce the function of a protein, or eliminate altogether. If a somatic mutation arises that reduces the function of the HER2 protein, or a similar protein that stimulates cellular replication (i.e. proto-oncogene), would this be a problem for the organism? Why or why not?

Yes, even though they play a role in cancer formation, proto-oncogenes serve a vital purpose to the cell. The HER2 protein ensures normal growth of epithelial cells. If these proteins were mutated and had reduced function it would greatly affect cell growth. *HER2 is necessary in the body and ONLY poses a threat to increased risk of cancer when it suffers a mutation that increases its function.

Cancer

a disease state characterized by uncontrolled cell division.

HER2

a proto-oncogene, stands for human epidermal growth factor receptor 2. the protein that it codes for plays an import role in the growth of epidermal tissue

Oncogenes

an allele whose protein products results in an increased rate of mitosis, which could lead to a cancerous tumor. also called "throttles" because their protein products act as an accelerator pedal that would speed up cell division

Apoptosis

biochemical process resulting in self destruction of the cell

Provide a list of cancers that have been associated with mutations in either BRCA1 or BRCA2.

breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer

Tumor Supressor Genes

can be thought of as "brakes," the proteins that these genes produce can help repair the damaged dna of a photo-oncogene. alternatively, the proteins of these genes can trigger the process of apoptosis when a mutation occurs in one of these genes, there's a chance that the associated protein loses the ability to keep potentially dangerous mutations in check

What errors could be found in the G2 checkpoint?

errors that have occurred during the replication of proto-oncogenes or tumor suppressor genes that are not corrected by p53, BRCA1 or BRCA2.

What are the different stages of cancer growth?

hyperplasia, dysplasia, in situ cancer/tumor

What percent of cancer occurrences feature a mutated form of the TP53 gene?

more than 50%

TP53

perhaps one of the most well-studied tumor suppressor genes, produces the protein p53

G1 phase

stage of interphase in which cell grows and performs its normal functions such as breaking down molecules and importing/exporting stuff.

Proto-Oncogenes

the earliest form of a gene that could mutate into an allele whose protein product could play a role in cancer forming

Why is cancer is exceedingly rare in elephants?

they have 20 copies of the TP53 gene in their dna. if one copy picks up a mutation its not a problem, they still have 19 copies of the gene that code for functional versions of TP53

HOW and WHY would cancer occur?

typically, the cells in our body have a predictable lifecycle and lifespan. However, this doesn't always happen. cancers occur when there are genetic mutations in a cell that result in either mitosis occurring far more often or apoptosis being much less likely to be initiated.

p53 protein

when the dna in a cell gets damaged this protein, acting in the nucleus, can do two things 1. if the dna can be repaired, the protein can activate other genes to produce proteins needed for that dna repair 2. if the dna cannot be repaired, the protein will prevent the cell from dividing, ultimately leading to apoptosis