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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
oÉ
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