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NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE Using Precision Medicine to Target Breast Cancer and the Cell Cycle Know Your Enemy, Know Yourself: d{" If you know the enemy and know yourself, you need not fear the result of a hundred battles. If you know yourself but Kelsie M. Bernot, Telah A. Wingate, & Kiara D. Whitaker not the enemy, for every victory gained you will also su ff er a Department of Biology defeat. If you know neither the enemy nor yourself, you will North Carolina A&T State University, Greensboro, NC succumb in every battle. —Sun Tzu, Th e Art of War Introduction Learning Objectives After completing this case study, you should be able to: Read and interpret breast cancer pathology results. Draw the phases of mitosis. Connect cell signaling to cell cycle regulation, and explain how dysregulation of those events can lead to cancer. Discuss how physicians use precision medicine to obtain genetic information about the individual’s tumor tissue to target treatment speci fi c to that individual’s cancer. Discuss how physicians use precision medicine to obtain genetic information about the individual’s somatic, non-cancerous cells to make decisions about treatment. De fi ne incidence and mortality . Compare how health disparities impact patients’ and physicians’ abilities to know the enemy and know themselves in the United States and the world. Discuss the impact of ethnicity, age, geographic location and healthcare infrastructure on health disparities. YOU ARE WELCOME TO ACCESS THESE, BUT THE MATERIAL IS PART OF THIS WEEK Please prepare for our class meeting by watching the following videos and taking notes on the phases of mitosis. Video 1: Hasudungan, A. 2013. Cell cycle (mitosis). Running time: 9:52 min. <https://youtu.be/DePnK9TwU6w>. Video 2: BiologySpotTutors. 2012. Cell cycle checkpoints. Running time: 3:44 min. <https://youtu.be/ eljbYQihxXw>. After watching these two videos you should be able to: Describe the cell cycle and what happens at each phase: G 0 , G 1 , S, G 2 , M, and cytokinesis. Describe the three cell cycle checkpoints, what is being detected at each checkpoint, and what happens to the cell if it does not meet the requirements of the checkpoint. Next, watch the following: Video 3: Bozeman Science. 2014. Phases of mitosis. Running time: 10:41 min. <https://youtu.be/mXVoTj06zwg>. You should now also be able to: List the phases of mitosis in the order in which they occur and describe what happens in each phase. Case copyright held by the National Center for Case Study Teaching in Science , University at Bu ff alo, State University of New York. Originally published October 15 , 2018 . Please see our usage guidelines , which outline our policy concerning permissible reproduction of this work. Photo © Richard FIsher, cc by 2 . 0 , <https://www. fl ickr.com/photos/richard fi sher/3415115671>.
NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE Part I – Uh-oh Kelly and her husband Jack were fooling around in bed one evening, when Jack felt a lump on Kelly’s breast. “What’s this?” he asked. Kelly replied, “Oh, I don’t know, it’s probably a cyst or something to do with my menstrual cycle.” At 33 years of age, Kelly wasn’t concerned about the lump and was certain it would go away; however, her gynocolo- gist wasn’t so sure. After a mammogram showed a suspicious mass, the radiologist ordered a biopsy , telling Kelly “It’s possible that this is a benign tumor; however we need to make certain that it is not malignant .” During the next two days while Kelly was waiting to hear the results of the biopsy, she felt anxious. She periodically felt adrenaline coursing through her body as she fi nally considered the possibility that she might have cancer . Questions 1. Explain the relationship between the following words: benign, malignant, biopsy, and cancer. If you have studied epinephrine (adrenalin) signaling previously (and you most certainly have) , consider why Kelly felt the effects of the hormone, adrenaline. What signals was this molecule sending to various parts of her body? (You may need to consult a reliable online source to fully understand the concept of how the hormone adrenalin acts on different tissues in the body.) “Know Your Enemy, Know Yourself” by Bernot, Wingate, & Whitaker Page 2 uncontrolled rate of cell proliferation that leads to benign doesn't spread into other tissues non cancerous destruction of neighboring mass of cells w no functional purpose tissue malignant cancerous can spread to other parts of the body uncontrolled division of cellsinvading other tissues biopsy a tissue removed to be analyzed to see if the cells are cancerous Kelly was worried that she had a malignant tumor so adrenaline can cause her heart rate to increase eyes to dilate etc increase temp inc respiration Of blood sugar level I glucose available to in cellular respirator glucose is stored as glycogen so you breakdown glycogen
NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE Part II – Results Getting o ff the phone with the radiologist is kind of strange because I’m about to say to my coworkers for the fi rst time, “I have cancer.” I test it out in my head, and it sounds really weird, but I go ahead and say it anyway. We spend a little time talking (me laughing about things, which seems kind of inappropriate, but that’s sometimes how I react to bad or sad news—I can’t seem to help it). A few coworkers o ff er to drive me home, but I want to fi nish my work. What am I going to do at home—sit and cry? Th at’s totally not my style, even if it would be understandable. Life hands you lemons, you gotta make lemonade—or at least put it in a bottle of Corona! — Kelly’s blog Th is news initiated a whirlwind of doctor’s visits: eight doctors in seven days—radiologist, two breast surgeons, an oncologist, three plastic surgeons, and a radiation oncologist. Kelly was a scientist, yet she felt as though she was study- ing for the most important exam in her life—deciding how to treat her breast cancer. Kelly underwent a mastectomy, during which the breast surgeon removed her cancerous breast and sent the tissue to pathology. Th e plastic surgeon then inserted a tissue expander, which would gradually stretch her skin over several months so that she could receive a breast implant to normalize her physical appearance. I really don’t care about losing a breast. I don’t need it for anything. It’s not like it’s my brain or even a kidney. Not only do I have two breasts, but they don’t do anything essential anyway, so what’s it matter if I have to get rid of one? I’m de fi nitely in mental and physical preparation for this journey. I feel like I do just before a race when I’m warning myself that’s it’s gonna hurt, and I’m gonna be exhausted, but I have to keep pushing my hardest. — Kelly’s blog Questions 1. Th e pathology report to the right is the exact information that Kelly received from the pathologist. Precision medicine requires the knowledge of factors that may di ff er between di ff erent cancers, even within the same type of cancer (e.g., breast cancer). Th is is a critical piece to “know your enemy.” Number 1 on the pathology report shows Kelly’s scores for various markers that determine the type and aggressiveness of Kelly’s cancer, and may provide targets for treatment with precision medicine. Numbers 2–4 on the report tell the reader how to interpret the results. Use this information to interpret Kelly’s results, scoring each of the following markers as low, high, positive, or negative. Note that this aspect of precision medicine is focused only on Kelly’s cancer cells and what di ff erences they have from normal cells that can be targeted by drugs. a. Ki-67 Proliferation Index _________________ b. Estrogen Receptor ______________________ c. Progesterone Receptor ___________________ d. Her2/Neu ____________________________ 2. Read this description of Ki-67 from Wikipedia: Th e Ki-67 protein (also known as MKI67) is a cellular marker for proliferation. It is strictly associated with cell proliferation. Ki-67 protein is Pathology Results In fi ltrating duct carcinoma Ductal carcinoma in situ Prominent lymphoid in fi ltrates 1. Characterization: a. Ki-67 Proliferation Index – 40% b. Estrogen Receptor - >90% with strong intensity c. Progesterone Receptor – 5% with strong intensity d. Her2/Neu – 3+ 2. Interpretation of Results – Ki-67 a. <10% = LOW b. >30% = HIGH 3. Interpretation of Results – Estrogen and Progesterone Receptors a. >10%, any intensity- POSITIVE b. <10%, strong or moderate – FOCALLY POSITIVE OR RARE POSITIVE c. 1-10%, weak-FOCALLY AND WEAKLY POSITIVE d. <1%, weak-NEGATIVE e. 0% - NEGATIVE 4. Interpretation of Results – Her2/Neu a. 0 = NEGATIVE (no staining) b. 1+ = NEGATIVE (weak, incomplete membrane staining or weak complete membrane staining in less than 10% of tumor cells) c. 2+ = EQUIVOCAL (complete membrane staining that is weak or non-uniform in more than 10% of tumor cells and/o4 intense complete membrane staining in less than 30% of tumor cells d. 3+ = POSITIVE (intense complete membrane staining in more than 30% of tumor cells) “Know Your Enemy, Know Yourself” by Bernot, Wingate, & Whitaker Page 3 high positive Éf positive weak was
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NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE present during all active phases of the cell cycle (G 1 , S, G 2 , and mitosis/cytokinesis), but is absent from resting cells (G 0 ). Ki-67 is an excellent marker to determine the growth fraction of a given cell population. Th e fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) is often correlated with the clinical course of cancer.” <http://en.wikipedia.org/wiki/Ki-67_(protein)>. Based on the Wikipedia description, does a high Ki-67 score mean that the cancer is more aggressive (growing faster) or less aggressive (growing slower)? 3. Estrogen receptor, progesterone receptor, and Her2/Neu (also known as epidermal growth factor receptor) are all signal transduction receptor proteins that transmit signals to the cell to divide. Predict the name of the ligand for each receptor. How could having too many growth factor receptors on the surface of the cell make a more aggressive cancer? 4. Some cells divide constantly, whereas other cells rarely divide if at all. Rank the following cell types by their frequency of cell division from never to constantly. a. Hair cells ________ b. Liver cells ________ c. Muscle cells ________ d. Sensory Neurons ________ 5. Review the phases of the cell cycle by placing the abbreviated phase name (G 1 , S, G 2 , or M/C) next to the event(s) that occur during that phase of the cell cycle. a. _____ Errors in DNA replication are repaired. b. _____ DNA is replicated. c. _____ Th e cell grows by producing more proteins and organelles. d. _____ Th e cell physically divides into two cells, with identical copies of DNA going into each new cell. 6. Review the three regulatory checkpoints that determine whether a cell progresses through the cell cycle, rests in G 0 , or undergoes programmed cell death (apoptosis). Checkpoint Name: What is the cell checking for at each checkpoint? What happens to cell if it can’t pass checkpoint? G 1 G /M 2 Metaphase (part of mitosis) “Know Your Enemy, Know Yourself” by Bernot, Wingate, & Whitaker Page 4 weare trying to see if cancerous cells are replicating too much there are any temporary in Go but the majority of µ cellsare held in Go ble mature cells in Go don't express ki 67 more aggressor theratio of Ki67 expressing cells ki 67 non expressing all should be low If your Ki62 here are highermore cells are reprinting when they shouldn't be of ligand estrogen for estrogen receptor ligand progesterone for progesterone receptor I 2 3 Jeff ed liver cells constantly never will grow back if you remove Yffety sensory neuronsc liver cells chair cells G Me If the cell wants to commit to cell division cell makes sure that the cell is equipped v1 necessary