Week 18 - Breast Cancer Flashcards
Describe how DNA replicates within the cell cycle
Interphase - G1, S, G2 - Growth, DNA replication and prep all happening
Mitosis - Prophase, Metaphase, Anaphase, Telophase
Cytokinesis- cytoplasm splitting
Describe the type of errors that can occur during cell cycle
Nucleotides damaged or matched up incorrectly
Point mutations
DNA amplification
Chromosomal rearrangement
Epigenetic modifications - methylation, etc.
Describe how errors that occur during cell cycle may be repaired, what consequences they have
Point mutations
DNA amplification
Chromosomal rearrangement
Epigenetic modifications - methylation, etc.
Mutations can allow cell to bypass checkpoints - by two main mechanisms - activating oncogenes (RAS, MYC) and deactivating tumour suppressor genes (BRCA, p53, APC)
FIXING ERRORS:
Proofreading - DNA polymerases can “check their work” with each base that they add.
Mismatch repair - after proofreading, a protein coplex comes through cutting away errors that were missed
Direct reversal of damage - some issues can be reversed
Base excision repair - specialised glycosylases remove specific pieces of damage
Non-homologeous end joining - gluing damaged bits together after breakge
Homologous end joining - Broken chromosome pairs with its homologue so piece is replaced
Outline cell cycle control mechanisms
Cell cycle ‘checkpoints’ - do not let process progress if any issues - controls progression from G1/S, G2/Mitosis, Metaphase/A
Mitogens - cytokines that stimulate cell proliferation
What is the relevance of cell cycle control mechanisms and their relevance to tumour development
Checkpoints, repair mechanisms
Mutations can allow cell to bypass checkpoints - by two main mechanisms - activating oncogenes (RAS, MYC) and deactivating tumour suppressor genes (BRCA, p53, APC)
RAS mutation means a lot of phosphorylation of proteins in the cell, which starts making a lot of CDK and cyclins
Mutations to tumour suppressor genes means that cells will no longer be able to make proteins that perform regulatory functions (like pausing growth/division, facilitating repairs and initiating apoptosis)
Outline the role and timing of two key tumour suppressor proteins
p53 - S phase - coded by TP53 which is ‘guardian of the genome’
pRb - G1/S phase - regulates transcription
What are the 4 stages of carcinogenesis?
Initiation, Promotion, Progression, Malignant conversion
What are the different types of carcinogens?
Chemical, physical and viral
What is the difference between proto-oncogenes and oncogenes?
Proto-oncogenes - normal cellular genes which regulate cell growth
Oncogenes - a proto-oncogene that has been activated by mutation or over-expression
Types of alterations that transform proto-oncogenes into oncogenes (3)
Point mutation
Gene amplification
Chromosomal translocation
What does HER2 need to be active?
Dimerisation (with itself or another)
Lind with ligand (human epidermal growth factor)
What are the treatment options for HER2+ cancers? (2)
Trastuzumab (Herceptin) and pertuzumab
Describe process of BCR-ABL1 mutation and treatment
In 95% of cases of myeloid leukaemia
Chromosomal translocation creates Philadelphia chromosome
BCR section now stimulates ABL section
Can be treated successfully with Imatinib
How does BRCA 1/2 work as a DNA repair gene?
Repair double strand breaks
(if it is mutated, there is nothing that fixes double strand breaks - as PARP only fixes single strand breaks which start to add up)
What is a PARP inhibitor?
PARP usually fixes single strand breaks
PARP inhibitors can be used in patients with BRCA mutation - the cells will not be able to repair single or double strand breaks and will collapse and initiate apoptosis
What is Rb and how does it work?
Retinoblastoma protein
Works in G1/S to regulate transcription
Binds to E2F which facilitates phosphorylation
What is a mitogen?
Cytokine (small protein) that stimulates cell proliferation - some of them are proto-oncogenes
Describe the cell cycle in cancer
PICTURE FROM FOLDER
What is phosphorylation?
Reversible protein phosphorylation, principally on serine, threonine or tyrosine residues, is one of the most important and well-studied post-translational modifications. Phosphorylation plays critical roles in the regulation of many cellular processes including cell cycle, growth, apoptosis and signal transduction pathways.
Phosphorylation is the most common mechanism of regulating protein function and transmitting signals throughout the cell.
Examples of non-neoplastic alterations in cell growth (5)
Hyperplasia - More of them Hypoplasia - Less of them Hypertropy - Bigger Atrophy - Smaller Metaplasia - Replacement with another cell type
All can be physiological or pathological
Types of cells (3)
Permanent
Stable
Labile
Define hyperplasia
Increase in tissue or organ size due to an increase in cell number
Define hypoplasia
A decrease in organ or tissue size due to loss of cells
Define hypertrophy
Enlargement because of increase in cell size
Define atrophy
Shrinkage of a tissue or organ due to loss of cells and decrease in cell size
Define metaplasia
Reversible replacement of one mature cell type with another
Define dysplasia
Pre-malignant state, characterised by disordered maturation of cells within a tissue
Looks like malignancy, still within epithelium (has not broken through basement membrane)
Benign vs malignant
Can’t vs can metastisise
Carcinoma, sarcoma (define)
Carcinoma - suffix applied to malignant epithelial tumours
Sarcoma - suffix applied to malignant connective tissue tumours
How do tumours develop? What kinds of things can cause this process?
Accumulation of mutations which over-ride the normal mechanisms which control cell proliferation.
Caused by things such as smoking, radiation, viruses, cancer-causing chemicals (carcinogens), obesity, hormones, chronic inflammation and a lack of exercise
Benign vs malignant microscopic features
PICTURE IN FOLDER
Outline types and locations of epithelium
Squamous - skin, GI tract
Cuboidal / columnar - glandular, hollow organs
Columnar - ureters, internal tubes
What is an adenocarcinoma?
Cancer of the glandular epithelium
Examples of non-epithelial tumours
Connective tissue tumours
PICTURE IN FOLDER
How do tumours spread?
- directly into adjacent tissues (eg basal cell Ca of skin)
- via lymphatics (eg Ca breast, colon)
- blood vessels (eg renal cell Ca, small cell Ca lung, prostatic Ca, all sarcomas)
- along nerves (eg Ca pancreas, prostate)
- across coelomic cavities (eg Ca stomach, ovary)
Example grading of tumours
well differentiated tumours (grade 1) resemble the tissue of origin and tend to behave less aggressively than poorly differentiated tumours (grade 3)
Describe TNM system
T= tumour, generally tumour size, eg Ca breast, T1 <2cm, T4 >5cm or tethered to skin
N= nodes. Regional lymph node involvement is N1, distant nodes N2
M=metastases: M0 none, M1 present, MX not known
