These questions address the Journal of Clinical Investigation article entitled “Breast Cancer:
Origins and Evolution” by Polyak (2007).
Be sure to explain your answers.
1.
Both your interview and your article mentioned
the hereditary factors involved in breast cancer. What is the h2 of breast cancer
thought to be? Both sources also
mentioned targeted therapies, especially focusing on pathways. How does this work?
a. When dealing with breast cancer,
hereditary factors are implied because one of the strongest determinants of
risk is based on family history. Studies have shown that mammographic breast
density is a highly heritable factor for breast cancer with h2>0.6.
It has also been found that major mutations such as BRCA1/2 and
TP53 cause a small percentage of heritable breast cancers. Targeted
therapies have high therapeutic efficacy with a small chance of side effects.
In order for a drug to be effective, it must identify tumor cell-specific
molecular pathways that change with the development of the drug. Targeting
these leads to a therapeutic response and clinical benefits. The targeted
therapies that focus on pathways has been shown to be a more viable therapeutic
approach then targeting individual genes.
2.
Most genes code for proteins. Given the information in this article and the
above question, why is it important to look at protein folding and mis-folding
when studying cancer?
a. It is very important to look at proper
protein folding in order to better understand the protein mis-folding that
leads to cancer. If we as researchers know these proteins in and out, then we
can eventually have the ability to stop the protein mis-foldings and hopefully
prevent tumor growth altogether. The more time and effort applied to understanding
the proteins, the closer we are to stopping the widespread disease of cancer.
b. When protein folds do not occur
correctly it mainly affects a protein called p53. This protein is located in
the body’s cancer resistance network. It is normally “switched off” but is
activated inside of the cell if the cell becomes stressed or damaged. Cell
damage can lead to genetic mutations in DNA that can cause uncontrolled
division and proliferation of cells that leads to tumor formation. The p53
works by heading to the cell nucleus and begins the production of other
proteins that stop the tumor formation or can trigger programmed cell death. A
slight mutation in one of the nucleotides in the gene can lead to p53 proteins
mis-folding. This leads to the p53 not carrying out its job and eventually
tumor cell growth. This mutation of p53 occurs in fifty percent of all cancer
cases and ninety-five percent of all lung cancer cases specifically.
3.
In an evolutionary sense, why is it informative
to study cancer and its implications in flies or, especially, in mice?
a.
Studies using mice or flies have the ability to
perform experiments that may be difficult, dangerous, or otherwise unethical to
perform on humans. Evolutionarily, humans, mice, and flies are made of the same
DNA and proteins that may be expressed in minor differences between them. In
this study specifically, human breast tissue and mouse breast tissue found to
have progenitor and stem cells, both of which are required for normal mammary
gland development. Studying mice pathways and the evolution of tumor
development can therefore give insight on human breast cancer tumor progression
and hopefully means of better treatment and prevention.
4.
Apply Darwin’s postulates to the
microenvironmental influences on breast cancer cells.
a.
Variation among individuals of the same species
i.
Not all tumor cells are comprised of exactly the
same amount of epithelial cells, leukocytes, fibroblasts, etc. in the
microenvironment. There are also differences in tumor cells as they progress
and develop including in situ, invasive, and metastatic carcinomas, which are
contributed by the changing cell microenvironment.
b.
At least some of these variations are hereditary
i.
Epigenetic changes (methylation, chromatin) were found in each cell type during
tumor progression. Tumor-associated stromal cells maintain their altered
phenotype in cells in subsequent generations, suggesting changes in
microenvironment to be permanent and heritable.
c.
Every generation has more offspring than can
survive
i.
We see that in breast tumor progression, while
the number of fibroblasts, myofibroblasts, lymphocytes, and endothelial cells
increases, the myoepithelial cells are altered and decrease in number.
d.
Natural selection operates on populations
i.
It’s possible that cancerous stem cell changes
and evolution during tumor progression drives selection and other
genetic/epigenetic factors allowing the survival and proliferation of the tumor
cell.
5.
The author asserts that tumor heterogeneity may
be the result of competition among cancer cells with different phenotypes. Why, then, might it be important for an
Oncologist to understand evolution?
a.
The genotype of the cells that cause the tumors
can be heterozygous due to two models. The first being that the cells started
out separately as separate cells then combined and the second being competition
among tumor cells. When cells compete, they are not as stable as they would be
without competition. Oncologists must understand the heterogeneity in order to
diagnose, treat, and then be able to detect the new tumor genotypes before they
evolve again. These genotypes constantly evolve because they are constantly
competing and undergo natural selection.
