Cell Signalling

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  • Created by: Lydia
  • Created on: 17-10-17 16:49
Breast cancer risk factors that cannot be changed
Age, gender, reproductive history, menstrual history, genetics, radiation, race, family history, treatment with diethylstilbestrol (DES- synthetic oestrogen)
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Breast cancer risk factors that can be changed
Increase risk: alcohol consumption, obesity, oral contraceptive, hormone replacement therapy after menopause / Decrease risk: having children, breast feeding, exercise
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What two type of cells to breast stem/ progenitor cells give rise to in ducts?
Luminal and basal cells
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Which type of breast cancer has the worst prognosis?
Triple Negative
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Which type of breast cancer has the best prognosis?
Luminal A
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Which receptors are expressed in Luminal A breast cancer?
ER+ and PR+
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Which receptors are expressed in Luminal B breast cancer?
ER+, PR+ and HER2
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Which receptors are expressed in HER2+ breast cancer?
HER2
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Name three endocrine therapies for breast cancer
Tamoxifen, ovarian ablation, aromatase inhibitors, selective estrogen receptor modulators (SERMs), herceptin
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Does ER alpha over-expression correlate with better or worse prognosis?
Better
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What kind of treatment does 50-70% of ER alpha + tumours respond to?
Endocrine (tamoxifen, aromatase inhibitors...)
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Which superfamily is ER alpha a member of?
Nuclear receptor transcription factors
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Explain the direct ligand dependent pathway of ER alpha regulation
Ligand binds to ER alpha => ER alpha-ligand complex bind directly onto DNA => Regulates transcription
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Explain the tethered ligand dependent pathway of ER alpha regulation
Ligand binds to ER alpha => ER alpha-ligand complex bind to a transcription factor => this complex binds to DNA and regulates transcription
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Explain the non-genomic ligand dependent pathway of ER alpha regulation
Ligand binds to ER alpha OR binds to membrane receptor which signals to activate cytosolic ER alpha => Secondary messengers are activated => signalling cascade => physiological effects
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Explain the growth factor signalling ligand independent pathway of ER alpha regulation
Growth factor binds to receptor => Activates kinases => Phosphorylated ER alpha binds to DNA and acts as transcription factor / secondary messenger cascades activated
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Name the domains of the ER alpha protein
AF1 (activation function 1), DBD (DNA binding domain), LBD (ligand binding domain) / AF2 (activation function 2)
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What is the ERE?
Estrogen Response Element- section of DNA in promoter region which binds estrogen receptor complex that regulates transcription
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Which proteins are in the estrogen receptor transcription complex?
ER alpha receptor, co-regulators, TAFs (TBP-associated factors), TBP (TATA binding protein), polymerase 2
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Name 2 molecules that can causes chromatin deconcentration and transcriptional derepression at the ERE
Estrogen and Cyclin D1
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What post translational modification of ER alpha allows for chromatin deconcentration and transcriptional derepression at the ERE?
Phosphorylation of AF1 domain
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What causes chromatin concentration and transcriptional repression at the ERE?
SERMs (selective estrogen receptor modulators)
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How many people were diagnosed with cancer in the UK in 2013?
352 197
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How many males were diagnosed with cancer in the UK in 2013?
179 000
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How many females were diagnosed with cancer in the UK in 2013?
173 000
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What percentage of cancer diagnoses were people aged 70+ between 2011-2013?
50%
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Since the late 1970s, by what percentage have cancer incidence rates increased by in Great Britain?
30%
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In 2013, what percentage of cancer incidences were breast, lung, bowel and prostate in the UK?
53%
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How many deaths from cancer were there in the UK in 2014?
163 000
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What proportion of cancer deaths are people aged 65+?
75%
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What proportion of cancer deaths are people aged 75+?
50%
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In 2013, what percentage of cancer deaths were breast, lung, bowel and prostate in the UK?
46%
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What percentage of cancer cases were breast cancer in the UK in 2013?
15%
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How many new cases of breast cancer were there in 2013 in the UK and how many were male?
53 696 (340 were male)
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How many deaths from breast cancer in the UK in 2014?
11 433
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What percentage of women survive with breast cancer for 10+ years?
78%
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What percentage of female breast cancer patients were diagnosed aged 65+ in the UK between 2011-2013?
46%
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What is the median age to be diagnosed with breast cancer in the UK?
55
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What proportion of all women will be diagnosed with breast cancer in their life times?
1/8
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What percentage of primary breast tumours express high levels of ER alpha?
80%
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What is the name of the enzyme that is activated to reveal genes by chromatin decondensation for transcriptional derepression?
HAT- histone acetyltransferase
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Name 2 SERMs
Tamoxifen and raloxifene
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What is the aim of ChIP?
To determine if a DNA binding protein binds to a specific location or sequence in DNA
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What is the pathway that leads to phosphorylation of the S104/ S106 residues on the AF1 domain of ER alpha?
Cyclin E- CDK2 complex
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What are the pathways that lead to phosphorylation of the S118/ S167 residues on the AF1 domain of ER alpha?
Tyosine kinase receptor activation => GRB2 => SOS => RAS => RAF => MEK => ERK => (RSK) OR PI3K (phosphatidylinositol-4,5-bisphosphate 3 kinase) => AKT OR general transcription factors TFIIH / CK2 (Casein kinase 2)
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What is the pathway that leads to the phosphorylation of the S236 residue in the DNA binding domain of ER alpha causing dimerisation?
GPCR activation => Adenylyl cyclase => PKA
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Which group of breast cancer patients are treated with aromatase inhibitors?
Post-menopausal women or women with ablated ovaries
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What are the side effects of aromatase inhibitors?
Musculoskeletal disorder / bone fractures
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What 2 reactions to aromatase catalyse?
Testosterone => Oestradiol and Androstenedione => Oestrone (Androgenic precursor => oestrogen)
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What are the side effects of tamoxifen?
Vaginal bleeding / hot flushes / endometrial cancer
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How does tamoxifen affect ER alpha receptor?
It blocks oestradiol from binding to the ER alpha
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Tamoxifen is a pro-drug. Define pro-drug.
Biologically inactive compound that is activated when it is metabolised in the body
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What is tamoxifen metabolised by?
Cytochrome p450 family
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Tamoxifen is metabolised by the cytochrome p450 family to form what?
Endoxifen (4-OHT)
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Other cards in this set

Card 2

Front

Breast cancer risk factors that can be changed

Back

Increase risk: alcohol consumption, obesity, oral contraceptive, hormone replacement therapy after menopause / Decrease risk: having children, breast feeding, exercise

Card 3

Front

What two type of cells to breast stem/ progenitor cells give rise to in ducts?

Back

Preview of the front of card 3

Card 4

Front

Which type of breast cancer has the worst prognosis?

Back

Preview of the front of card 4

Card 5

Front

Which type of breast cancer has the best prognosis?

Back

Preview of the front of card 5
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