CASE 7 Flashcards
what changes occur as cancer develops?
increased number of cells:
- increased cell division
- cell survival/immortalisation
- cell growth
describe the G0 cell cycle stage
where cells differentiate — most cells are in this stage. some cells can leave and re enter this stage (cells that are lost cannot be replaced)
describe G1 and G2 phases of the cell cycle
cell grows — produces extra organelles to split between daughter cells
what happens in S phase of the cell cycle
DNA replication
when does cyclin B expression peak?
in mitosis
what does cyclin B associate with and why?
cyclin B first associates with cyclin dependent kinase 1 (CDK1) to activate CDK1
what is the role of CDK1?
the kinase is present throughout the cell cycle, it phosphorylates other proteins but ONLY when it is i a complex with cyclin B which is present in the transition form G2 to mitosis
what does the CDK1 - cyclin B complex do?
the CDK1 activates and phosphorylates other proteins eg. Histone 1 (chromosome condensation), ,MAP (spindle formation), lamin (nuclear envelope breakdown) — all seen as cells exit G2 and go into prophase
what is the cyclin D/CDK4 complex required for?
progression of G0 to G1
what is the cyclin E/CDK2 complex required for?
progression from G1 to S phase
what is the cyclin A/CDK2 complex required for?
sustain interphase so all DNA is replicated
what is the cyclin A/CDK1 complex required for?
also plays role in progression of G2 to mitosis like the cyclin B/CDK1 complex
what is necrosis?
accidental cell death due to injury which releases cellular contents leading to an inflammatory response when the spilled out cellular contents come into contact with neighbouring cells
what is apoptosis?
the organised destruction of a cell which is initiated by either a signal from a neighbouring cell or the cell itself due to sensed internal damage. this process does not cause an inflammatory response and is common to referred to as programmed cell death.
why is there no inflammatory response in apoptosis?
always in a vesicle surrounded by a membrane
describe the process of apoptosis
- chromosomes will condense inside the cell
- fragmentation of the nucleus
- breakdown of cytoskeleton causing the cell to round up and start to bleb and release vesicles containing the cellular contents surrounded by a membrane — never released into surrounding environment
- these vesicles are phagocytosed by neighbouring cells and the contents are broken down into the basic amino acids, lipids, carbs, and nucleic acids for recycling in the neighbouring cell
what is TNFa?
= tumour necrosis factor a (alpha)
what does TNFa do?
binds to receptors on neighbouring cells, causing those receptors to trimerise — forms a trimer (3 receptor molecules), allows recruitment of intracellular proteins to make a signalling complex on intracellular side = DISC (death induced signalling complex)
what does disc activate?
(death induced signalling complex) activates a series of proteases
what do caspases do? what is inevitable once they are activated?
they degrade proteins in cell to cause to lead to cell death — apoptosis is inevitable once they are activated
what is bax and what does it do when stimulated by intracellular signals?
it is a apoptosis regulator — intracellular signals cause Bax to relocate from cytoplasm to outer membrane of mitochondria— forms a pore in membrane — allows a release of proteins found within the intermembranous space between the outer membrane and inner membrane of mitochondria
what do the released proteins from the mitochondrial intermembranous space do?
activate caspases — APOPTOSIS
what is myc? result of decreasing its function?
= a protein which controls cell growth
reducing myc function decreases cell size
mutations in what leads to tumour development?
proto-oncogenes and tumour suppressor genes
what do proto-oncogenes do?
promote cell division, survival and growth, cell proliferation
does a mutation in proto-oncogenes increase or decrease function? what kind of mutation?
protein function increased by mutation. DOMINANT mutation
what is the name of an activated proto-oncogene?
oncogene
give examples of a proto-oncogene in breast cancer
- ER (estrogen receptor)
- HER2
what do tumour suppressor genes do?
inhibit progression through cell cycle — promote apoptosis and inhibit cell growth
does a mutation in a tumour suppressor gene increase or decrease protein function? what kind of mutation?
protein function is reduced by mutation — RECESSIVE mutation
list examples of tumour suppressor genes
- BRCA1
- p53
what is worse, the loss of TSG or the activation of oncogenes?
the loss of tumour suppressor genes is worse
what is HER2?
= Human Epidermal Growth Factor 2
- HER2 gene encodes a plasma membrane protein which acts as a receptor for EGF = epidermal growth factor
in the presence of EGF, what does HER2 do?
Her2 dimerises with a 2nd plasma protein called Her1 — recruits a complex from cytoplasm (Grb2 + Sos)
what does Sos do?
activates another protein attached to plasma membrane = ras
what does ras do?
ras signals (through a cascade of kinases) to cause the phosphorylation of a transcription factor ETS — allows it to associate and bind to DNA and promote transcription of the target gene
ras — raf — mek — erk — ets (phosphorylated)
why is EGF important in breast epithelium?
it is a very important signal within breast epithelium to promote cell proliferation to replace the ductal epithelium and the epithelium of the alveoli in the breast
over expression of HER2 in mammary epithelial cells cannot cause tumour formation in the absence of what?
cyclin D1 (plays a central role in the regulation of proliferation, linking the extracellular signaling environment to cell cycle progression)
is HER2 positive breast cancer hereditary?
no, unlike BRCA1/2 — it is a somatic mutation
test for Her2?
IMMUNOCYTOCHEMISTRY — uses antibodies that target specific peptides or protein antigens. these bound antibodies can then be detected using several different methods. biopsy taken to obtain tissue sample - tested to see if the cells have HER2 on their surface
BRCA1 is located on what chromosome?
chromosome 17
germline vs. somatic mutation
a germline mutation is inherited so is therefore present i every cell in your body. a somatic mutation is acquired later in life, causing damage to a gene in one cell at a time
BRCA1/2 mutation is what type of inheritance?
autosomal dominant
what does BRCA1 gene normally do?
normally synthesises protein called breast cancer type 1 susceptibility protein — responsible for DNA repair. this function is lost if mutated
what is SNP?
= single nucleotide polymorphism
not a mutation which truncates and stops the protein functioning, but rather a slight alteration in the protien — protein still manufactured
list environmental risk factors linked to breast cancer
- overweight — 9% increases risk
- alcohol — 6% increases risk
- physical inactivity — 5% increases risk
- smoking — 4% increases risk
- suboptimal diet — 3% increases risk
list hormonal factors linked to breast cancer
- breast feeding — decreases risk
- lower age at 1st child — decreases risk
- early menarche — increase risk
- late menopause — increases risk
- contraceptive pill — increases risk
- combined HRT — increases risk