Breast Cancer: Origins and Evolution Q&A

These questions address the Journal of Clinical Investigation article entitled “Breast Cancer: Origins and Evolution” by Polyak (2007).  

1. Your article mentions 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?

The h² of breast cancer is less than 25 percent, with most breast cancers being caused by low-penetrance genes. Making more targeted therapies, that promise high therapeutic efficacy with minimal side effects, would focus on the molecular pathways that are amenable to drug development, such as kinases. Focusing solely on kinases or sequencing all of the genes that have been indicated in breast cancer is the prominent studies currently. Sequencing all of the genes characterized has revealed that there are a high number of mutations, while the mutations in the tumor are low. To further the therapy tumors of every type would have to be sequenced. Following the sequencing, testing to discover the functional importance of the genes would the next step. Because of the number of mutations this is incredibly overwhelming, but mutations that are seen in a limited number of pathways such as PI3KCA/AKT/PTEN pathway indicated that targeting the pathway might be a viable approach. 

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?

Most genes code for proteins. Therefore, a small error or mutation in a gene could lead to an incomplete folding of a protein, which affects its function. When studying proteins, one must remember that shape determines function. If a protein is misfolded, the entire function will be changed. Over time, more and more research has been completed looking at the mechanisms of protein folding. Researchers have gained a better understanding of how the genetic blueprint of a protein relates to its biological function.  It has also become clear that wrongly folded proteins are involved in the development of many diseases, such as cancer.  For example, protein misfolding is thought to be the cause of the malfunctioning of p53. A lack of a correctly folded protein inhibits the tumor-suppressing function of p53. The protein p53 occupies the most important position in the body’s “cancer resistance network” and is such an important protein that it has been described as the “guardian of the genome.”  A mutation causing protein misfolding in p53 is thought to occur in 50% of all cases of cancer and as high as 95% of all cases of lung cancer. If we can discover what kind of mutation can cause cancerous cells then we can try to prevent said mutations. We know germ line mutations in “moderate- and low-penetrance genes is likely to explain the majority of cases.”[1] It is also evident that the number of genes mutated in breast cancer is high. Because of this, it is important to continue studying the relationship between the genome and protein function in regards to cancer.  Specially, we need to study protein mis-folding, because there is a high chance that there are multiple ways that proteins can mis-fold and create a cancerous cell.

3. In an evolutionary sense, why is it informative to study cancer and its implications in flies or, especially, in mice?

In general, both fruit flies and mice are good model organisms for experiments.  They are model organisms due to their similar genetic information as humans, and that they are able to reproduce quickly, allowing the studying of generations.  They are both also easy to keep in labs and to keep happy and alive.  For cancer in particular, although fruit flies and mice cannot acquire the same cancer forms as humans, their tissue growth and development can help scientists find better treatments and preventions.  Mice, especially, are the leading models for cancer research by planting tumors and measuring growth and their more similar genetic makeup.  In this study on breast cancer, mouse breast tissue was used because it is composed of tumor and progenitor cells that are similar to humans breast tissue.

4. Apply Darwin’s postulates to the micro environmental influences on breast cancer cells.

Darwin’s postulates are used to describe how a new species can come into existence through the existence of variation and natural selection for or against that variation. The first postulate states that there is variation among individuals of the same species. Applying this postulate to breast cancer, we see that some cancer cells showed differences in the methylation of their DNA sequences. The methylation process is when a methyl group (-CH3) is added to a cytosine molecules in the DNA sequence. This can cause the suppression of certain genes (DNA methylation). Homeobox genes have been seen to be specifically affected by this methylation process. This observation points to connections between the normal methylation and the cancer-associated microenvironment cells and the differences seen among the different cancer cells.

The second postulate states that some of this variation that is seen is heritable, meaning it can be passed down through the generations. If heritable, then this would mean that as the cancer cells began to replicate further within the tissues through mitosis, each individual daughter cell from the original parental cell would have the same genetic disposition of the methylation process because the trait would be passed down through the generations. So if one cancer cell was to have a suppression of an apoptotic gene due to methylation, there would be noting to trigger cell death and the cell would keep dividing and producing more copies of itself unless an outside source intervened to stop the process.

The third postulate states that in every generation of the species there are more offspring produced than can actually survive in that environment. Going back to breast cancer, this would indicate that for each replication phase, or generation, of cancer cell some of these cells would die. This could be from problems in the mitotic division leading to an unstable cell that could not survive. This could also be to the variation in a certain gene, like the methylation of cytosine. This phenotype could lead to the death of the cell or it could lead to a rapid fixation, or spreading, depending on if it was selected for or against for the environment that it was in.

The fourth postulate states natural selection will act on the population and select for or against this heritable variation. In the case of a methylation causing a suppression of a gene, the example was for this mutation to cause the suppression of an apoptotic pathway. If this trait was selected for, the trait would be continued to be passed down through each mitotic division the cells went through. If this example were to occur, it would be problematic for the patient because it would be difficult to kill the cells quickly if the cells own DNA lack the ability to signal cell death itself. The cells could begin to replicate faster than the treatment would need to destroy the amount of cells within the tissues.

The last postulate states that with the accumulation of multiple adaptations, those individuals within the population will eventually become a new species. This would mean that if the adaptation were to continue, eventually it could become a specific trait for a group of breast cancer cells and become a new subgroup or another species of cancer altogether. In breast cancer there has been five molecular sub-types of breast cancer that could have been distinguished through this process of natural selection through Darwin’s postulates.

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?

Breast cancer is not considered to be a single disease. It has been observed to be heterogenetic at the molecular and clinical levels. This means that there is a combination of traits that go into creating the overall phenotype of the specific cancer. There have been five sub-types found so far: basal-like, luminal A, luminal B, HER2⁺/ER^-, and normal breast-like. The differences among the sub-types determine what stem cell origin they arise from, what cancer pathway they will take, and how they will react to clinical treatments. It has been hypothesized that that competition among cancer cells can causes the different phenotypes to arise. It is thought to be possible that the cancer stem cells change themselves by undergoing clonal evolution during the tumor’s growth and progression that follows therapeutic treatments; this would mean that the stem cell-like ability of the cancer cells could be the driving force in the selection process of cancer cells that survive and replicate within the tissue. As an oncologist, it would be helpful to understand how evolution occurs because it seems that cancer cells themselves can have adaptive characteristics rather than the population as a whole. If a select number of cancer cells are resistant to a drug therapy, they will survive treatment and continue to replicate causing a new line of cancer cells to be present that will no longer be affected by the treatment. The oncologist would then have to proceed with another treatment option to kill the resistant strain of cells. With the stem cell like ability of the cancer cells allowing the cells to adapt to their environment quicker, an oncologist must stay ahead of the cancer’s pace so that it does not metastasize to other locations within the body. For the best interests of the patient it would then be beneficial for the oncologist to understand at least the basics of heritability and evolution.

Works Cited

Polyak, Kornelia. "Abstract." National Center for Biotechnology Information. U.S. National Library of Medicine, 01 Nov. 2007. Web. 07 Apr. 2014.

"DNA methylation." The American Heritage® New Dictionary of Cultural Literacy, Third Edition. Houghton Mifflin Company, 2005. 28 Mar. 2014. <Dictionary.com http://dictionary.reference.com/browse/DNA methylation>.

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