Summary and Statistics

Throughout this project, we learned about the background of breast cancer, the evolution of the disease, how prions, genetics, and model organisms relate to cancer, and in a more general sense, the importance of grid computing. 

We each have had friends and family members affected by this illness, and are happy that we could help in even a small way by joining BIOINC World Community Breast Cancer grid. On this grid we completed 678.94 units of work. One of the most exciting things about joining the grid was seeing accomplishments be achieved. While there were no major breakthroughs specific to breast cancer yet, our grid contributed to other fields. In February, a drug to combat neuroblastoma in children was discovered. Because of grid computing it had been shown to have little to no side effects. Currently the team is working with pharmaceutical companies to get the drug out into the field.

Grid computing is an easy, yet meaningful way to get involved in research, it is a simple way that everyone could easily help thousands of people through research and learn more about a disease or other topic of research that interests them. We strongly encourage signing up for a grid. The grid project itself was a wonderful way to connect the concepts we are learning in class to diseases and illnesses. It helped us to understand how important evolutionary concepts are. Even if you are not going to be an evolutionary biologist, the concepts are applicable to many fields, especially health care. 

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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Interview

A Breast Cancer Survivor’s Journey

“I will do anything to help others afflicted by cancer. Encouragement, support. That’s why God made me go through this, so I can help other women.” – Dana Brown

Dana Brown’s story serves as an inspiration. It was April 2013 when she learned she had the most common form of breast cancer, Invasive Ductal Carcinoma. At her yearly mammogram, a lump was detected in her left breast. She went underwent needle biopsy and discovered the tumor was malignant.

“Once you hear the ‘c word’ and it pertains to you, it is terrifying. But, you can either face it head on, or let it overtake you.” - Dana

Dana chose to fight. Because she had a hormone-driven tumor, she underwent breast-conserving therapy. Also known as a lumpectomy, this surgery removes part of the breast tissue, as opposed to the entire breast. Then, a genetic test, onco-dx, looked at 17 genes in the tumor to determine if chemotherapy was needed or not. The results of the test fell right in the middle. Therefore, another test, mamaprint, was used to assess the risk that the tumor will metastasize to other parts of the body. It was discovered she was at high risk for reoccurrence and would require chemotherapy.

She underwent four rounds of chemotherapy. The medicine used to heighten her immune system gave her such back pain it felt like labor.  She experienced high levels of fatigue, but minimal nausea and vomiting. Then, she underwent 30 rounds of radiation, one everyday for almost 6 weeks. Demonstrating what a strong woman she is, she said the radiation was “nothing compared to chemo.” She had burn symptoms, similar to sunburn, and her fingernails were damaged.

She described her treatment as “a journey, with ups and downs.” She said she got through it was help from family and a support group.

After the radiation, she felt a lump in the same breast. Thankfully, it was only scar tissue and no cancer was detected. She exercises through the Live Strong program to build her strength, bones, and muscle mass back up. Now, she is on an estrogen blocker for 5 years and her 6-month follow up is coming up.

And in the words of Dana, “Well that’s my story, and I’m sticking to it.”

During our interview, Dana gave impressive, thoughtful answers that showed her strength not only as a survivor, but also as a mother and woman. She was extremely knowledgeable, gracious, and loving. We laughed, got teary eyed, and even said "You go girl!" a few times out loud.

We thank Dana for her time and honesty. We dedicate this research project in honor of her and all other lives touched by this dreadful disease.

For cancer survivors and caregivers, Relay For Life is an opportunity to connect with others who are facing the same challenges. If you would like to donate to finish the fight, volunteer, or join a team, click on the following link: http://www.relayforlife.org/.

In addition, please take care to have regular self-breast exams and mammograms.

Introduction to our grid project

            Grid computing is a computer system where interconnected machines take advantage of each other’s resources, such as processing power, memory, and data storage.  In a grid, the computers are controlled separately and can perform tasks unrelated to the grid. The programs can be run in the background of the computer and can be made invisible to the user. The grids themselves vary in size. It could be as small as a group of computer workstations in a business, or, as large as many companies networking together.[1]

            Grid computing can benefit our world in ways no lab could ever recreate.  It can be used on an array of disciplines ranging from medicine to economics. The higher computing provided by grids allows for a common goal, often a complex mathematical or scientific calculation, to be accomplished more efficiently and quickly. Just like a manager of a store distributes work among employees, grid computing shares the workload across multiple computers. This way, there is a bigger pool of resources and less work has to be done by each machine. Typically, a computer can only utilize its own resources, limiting the speed and quality at which it can operate. However, grid computing allows one computer to access the collected power of all the networked computers, essentially creating one supercomputer. 

            For example, the world's largest non-profit computing grid, World Community Grid, connects volunteers' devices from across the globe. They claim, “That innovation combined with visionary scientific research and large-scale volunteerism can help make the planet smarter.” The grid-computing project we are involved in aims to identify the different chemical markers associated with many types of cancer. Finding the markers will allow for earlier detection of cancer, as well as more personalized cancer care. In order to participate, one can download and install secure, free software on a computer, smartphone or tablet by clicking on the following link: http://www.worldcommunitygrid.org/

Breast Cancer Overview

a)     Symptoms

i)      In early stages a person normally show no signs of symptoms

ii)    The first major sign of breast cancer is the appearance of small, painless lumps in the breast or underarm regions of the body

iii)   Pain or tenderness of the breasts may occur along with a change in size, texture, or shaping of the breasts

iv)    A change in the nipple area such as dimpling, itching, burning, or ulcerations

v)    Paget’s disease, a scaly rash of the nipple region can be linked to early signs of an underlying cancer

http://www.cancer.gov/cancertopics/screening/understanding-breast-changes/page6

b)    Diagnostic tests

i)      Mammogram

(1)  Most effective way to find lumps within the breast region

ii)    Self examination

(1)  Look for any signs of changes in the symmetry of the breasts

(2)  Check for lumps near the surface of the breast by pressing lighting around the region and increase pressure to check for lumps in deeper tissue

iii)   Ultrasound

(1)  Best way to determine if a lump is just a benign cyst or if it is a cancerous tumor

iv)   Biopsy

(1)  Best way to confirm a diagnosis of breast cancer by taking a sample of the tissue within the lump

http://www.peoplesdailyng.com/maitama-district-hospital-commissions-mammography-machine-ent-unit/

c)     Treatment

i)      Determined by the size of the tumor, the extent of the disease (spreading), as well as general factors such as age and pre-existing health issues

ii)    Most common forms of treatment:

(1)  Localized (within the breast and surrounding regions)

(a)   Surgery: removes the cancerous tissue

(b)  Radiation therapy: uses high levels of radiation to kill cancerous cells or to prevent spreading

(2)  Systemic (throughout the body)

(a)   Chemotherapy: drug therapy to kill cancerous cells, but has many side effects such as nausea, hair loss, and low blood counts

(b)  Hormone therapy: uses drugs to prevent certain hormones from promoting the growth of the cancer cells and it usually used after surgical treatments

Breast Cancer and grid computing sources

• http://www.cancer.org/healthy/morewaysacshelpsyoustaywell/breastcancer?gclid=COHQ3IS1hbwCFUtp7AodVmEAxQ

• http://www.webmd.com/breast-cancer/

• http://www.bcrfcure.org/

•  http://www.hopkinsmedicine.org/healthlibrary/test_procedures/gynecology/mammogram_procedure_92,P07781/

• http://www.medicinenet.com/mammogram/article.htm

• http://www.worldcommunitygrid.org/about_us/viewGridComputingBasics.do

• http://computer.howstuffworks.com/grid-computing.htm