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11711 Advanced Signaling
UC MED 2015
46
Medical
Graduate
11/09/2011

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Term
What are the Polyposis syndromes that predispose one to colorectal cancer?
Definition
1) Adenomatus polyposis coli (APC)
2) Attenuated adenomatous polyposis coli
3) Gardner's syndrome
4) Turcot's syndrome
Term
What are the Non-polyposis syndromes that predispose one to colorectal cancer?
Definition
1) Hereditary non-polyposis colon cancer (HNPCC)
Term
What are the Hamaratomatous syndromes that predispose one to colorectal cancer?
Definition
1) Cowden's syndrome
2) Familial juvenile polyposis syndrome
3) Peutz-Jaegher syndrome
Term
What percentage of colon cancers come from inherited mutations?
Definition
roughly 10%, the rest are from spontaneous mutations
Term
What are the major inherited colon cancers?
Definition
1) FAP (Familial adenomatous polyposis coli (APC)- 1% of all colon cancers
2) HNPCC (Hereditary non-polyposis colorectal cancer syndrome (4-10% of all colon cancers)
Term
FAP
1) What type of disorder?
2) Affects how many individuals?
3) Average age of onset/life expectancy
4) Avg number of adenomatous polyps
5) This leads to what other disorders?
Definition
1) Autosomal dominant disorder with complete penetrance (tumor supressor)
2) Affects 1 in 10,000 individuals
3) Onset is 39 and life expectancy is 42
4) avg number of adenomatous polyps is 1000
5) Also have stomach and duodenum polyps, bone tumors, and teeth abnormalities
Term
Where is APC located and what is the most typical problem that leads to its mis expression?
Definition
Location 5q, mostly have truncated proteins
Term
What is the clinical description of HNPCC?
Definition
-Right-sided or proximal colon adenocarcinoma
- Three affected first-degree relatives in two generations
-Age of onset below 50
-Other tumors including urothelium or endometrium
Term
In colorectal tumorigenesis, mutations in APC seem to be the initiating mutation followed by?
Definition
1) hypomethylation (increased transcription)
2) mutations in ras
3) mutations in dcc
4) mutations in p53
Term
What are the biological functions of APC?
Definition
1) Binds cytoplasmic ß-catenin, which is a transcription activator, and promotes ß-catenin degradation. This complex also contains axin (required for axis formation) and glycogen synthase 3ß kinase.

2) Binds to microtubules and aids in the assembly of kinetochores (allows connection of microtubules to centromeres of chromosomes, to pull sister chromatids apart as cells divide)

3) involved in regulation of Wnt signaling pathway
Term
What does the Wnt pathway do?
Definition
1) Wnt pathway controls cell fate during embryonic development
2) Wnt pathway is a key regulator of homeostasis in adult self-renewing tissues(such as the colonic epithelium)
Term
How do mutations in APC affect the Wnt pathway?
Definition
1) Most mutations produce truncated/non-functional APC
2) The axin complex never forms and ß-catenin cannot be phosphorylated and degraded
3) This leads to activation of TCF, and with APC defective, TCF is not removed from the nucleus
4) Constant stimulation of the Wnt pathway results

sidenote- APC is also involved in kinetochore function; its absence leads to genomic instability, as during mitosis aberrant chromosome segregation may occur
Term
TCF is inactivated by binding of?
Definition
Groucho
Term
ß-catenin is recognized by tagged for destruction by?
Definition
ß-TrCP
Term
What is part of the destruction complex when there is no Wnt signaling?
Definition
ß-CAT, Axin, APC, GSK3ß, CKI
Term
How many women will develop breast cancer is a year? men?
Definition
women 200,000- of which 43,000 die
men-1,600
Term
What percentage of breast cancers are familial?
Definition
10% of which 45% are related to BRCA1
Term
What is clinical description of BRCA1 breast cancer?
Definition
1) early age of onset
2) multiple family members with the same type of cancer
3) Bilateral or multiple tumors (breast and ovarian tumors in women, maybe prostate in men still controversial)
4) Absence of male breast cancer
Term
BRCA1 is what % penetrant?
Definition
85%
Term
BRCA1 is what type of gene?
Definition
A tumor supressor gene, in familial cases a loss of heterozygosity occurs.

Over 200 germline mutations making it difficult to screen and most mutations lead to truncations.
Term
DNA activates these kinases, which lead to phosphorylation of BRCA1?
Definition
1) ATM-IR damage
2) ATR- UV/HU damage
3) CHK2- ?
Term
What does phosphorylated BRCA1 do?
Definition
It can inhibit cell cycle progression, and error=prone repair of double-strand breaks in DNA
Term
BRCA1 also is known to associate with which other proteins?
Definition
1) BARD1- ubiquitin ligase activity-TF's are degraded so BRCA1 can assemble repair complex on DNA
2) ZBRK!- corepressor to maintain low levels of proteins necessary for DNA repair
Term
55% of familial breast cancer cases occur from?
Definition
BRCA2 mutations-men and women with breast cancer, women with ovaria cancer, multiple family members with cancer
Term
Tell me more about BRCA2?
Definition
-found by linkage analysis
-Chromosome 13, region q12-13
-Tumor supressor (as is BRCA1)
-Unlike colon cancer, non-familial breast cancer does not contain BRCA1 or BRCA2 mutations
Term
What does BRCA2 do?
Definition
-Involved in DNA ds breaks (as caused by ionizing radiation)
-Involved in transcriptional regulation w/ BRCA1 (very complex, involved with p53 in regulating genes involved in arresting the cell cycle until the DNA damage is repaired)
-BRCA2 is in all cells – it is still unclear as to why the breast and ovary are primarily targeted with BRCA1 and BRCA2 mutations, except for the estrogen responsiveness
Term
When BRCA1 is phosphorylated by ATM, what is recruited to help with repair?
Definition
BRCA2 and Rad51
Term
What interferes with estrogen binding to the estrogen receptor?
-It is classified as a SERM (selective estrogen receptor modulator)
-SERMs inhibit estrogen action in breast cells, but act as agonists for other tissues, such as the bone and liver (no osteoporosis, cholesterol levels stay low)
Definition
Tamoxifen
Term
What stimulates the growth of breast epithelial cells?
Definition
estrogen
Term
When is Tamoxifen used for?
Definition
1) To prevent breast cancer in younger women with an increased risk of the disease (49% reduction in tumors reported in one study, as compared to control) (5 years on the drug)
2) As an adjuvant to surgery, to prevent recurrence of the tumor
3) As treatment for advanced breast cancer
Term
What are the side effects of Tamoxifen?
Definition
1) Increased risk for blood clots
2) If pre-menopausal, brings on menopausal symptoms
3) Increases risk of endometrial cancer and uterine sarcomas
Term
What is a monoclonal antibody to HER2 receptor (the EGF receptor)?
Definition
Herceptin

1) HER2 is often over-expressed in metastatic breast cancer (20% of breast cancers)
2) The antibody blocks EGF binding to the receptor, thereby decreasing the rate of growth of the cells. Once bound, the antibody also recruits immune cells to the site of the tumor for destruction of the tumor cells
Term
What are some of the side effects of Herceptin?
Definition
1) Cardiomyopathy (left ventricular heart failure)
2) Hypersensitivity reactions
Term
What has poor prognosis – negative for estrogen receptor, HER-2 (human epidermal growth factor receptor-2) and progesterone receptor?
-Tamoxifen, Herceptin will not work on these cells due to lack of appropriate receptors
-Treatment has been surgery, chemotherapy, radiation – but not very successful
-New treatments have been devised – PARP inhibitors
Definition
Triple negative breast cancer cells
Term
What are the two forms of repair in ds breaks in DNA?
Definition
1) Homologous recombination(HR-occurs in S and G2 as a pair of sister chromatids is required.)
2) Non-homologous end-joining (NHEJ- occurs in the other phases of cell cycle)
Term
Of the two ds breaks in DNA, what one is better?
Definition
HR-not ewrror prone
NHEJ- is error prone
Term
What produces large chains of ADP at the ends of single chain breaks in DNA – used as a recognition signal by the repair enzymes (substrate is NAD+)?
Definition
PARP-1 (poly (ADP) ribose polymerase)
Term
What is responsible for 9% of cancer deaths in men?
Definition
prostate cancer-second most common cancer in men-first is lung cancer
Term
Who are more likely to get prostate cancer?
Definition
African-american men 61% more likely than caucasians and 2.5 times more likely to die
Term
What are your risks for getting prostate cancer, depending on your age range?
1-less than 40
2-40-59
3-60-79
4- chance in lifetime
Definition
1- 1 in 10,000
2- 1 in 45
3- 1 in 7
4- 1 in 6
Term
Microarray experiments have identified two "candidate" genes for prostate cancer, they come from which two pathways?
Definition
1) PTEN pathway
2) Sonic Hedgehog pathway
Term
What antagonizes the PI3K/AKT pathway by converting PIP3 to PIP2, thereby losing the ability to activate AKT(tumor suppressor)?
Definition
PTEN(phosphatase and tensin homolog)
Term
Loss of PTEN does what?
Definition
Constitutive action of AKT kinase(PKB)- which leads to a resistance to apoptosis via BAD phosphorylation
Term
What happens in the absence of hedgehog signal?
Definition
the patched receptor inhibits smoothened from activating the transcription factor GL 1.
Term
What does GL 1 do when activated?
Definition
it does gene transcription leading to cell growth
Term
Smoothened can be phosphorylated by _____ and also interacts with?
Definition
PKA

G proteins
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