Hormones and cancer Flashcards
Briefly summarise hormone involvement in breast cancer
Oestrogen has a major role in development and progression of disease
70% of cancers express oestrogen receptor (ER) and/or progesterone receptor
Describe the oestrogen receptor (ER)
Associated with co-repressors in thee nucleus, HSP90
E2 steriod passes through the membrane causes dimerization and phoispohorylation and increases binding of coactivators so it can bind to DNA
Transcriptional Activator Factor (TAF) 1&2 regions within receptor activated and increases gene transcription and tumour growth
What are SERMs?
Selective oestrogen receptor modulators
Eg Tamoxifen
Actively blocks TAF2 leaves TAF1 results in partially inactivated transcription and reduced rate of tumour growth
20mg of tamoxifen a day -no benefit to increase dose
Better than just chemo alone
SE- menopausal symptoms like hot flushes and sweats, fatigue, painful joints, initial nausea
All Tumours eventually become resistant- mutation in ER- receptor activation in absence of ligand, E2 independent phosphorylation, hyper sensitivity to ligand, isoform variation, non-genomic effects of oestrogen
Describe the non-genomic effects of oestrogen
Oestrogen can be present in the cytoplasm
➡SARC➡ PELP➡ PKC➡ MAPK
MAPK activates nuclear ER and AP1 transcription complex
PELP is a ER co-activator, scaffolding protein coupling signalling complexes with ER
Assoiciages with chromatin and involved in histone function
Couples ER to SRC and hence ERK
Found in the cytoplasm of early and aggressive tumour cells- tamoxifen resistant
What are aromatase inhibitors?
Local oestrogen levels controlled by conversion of oestrone to oestrodiol in tissues by aromatase enzymes
Increases E2 and therefore tumour growth
Inhibit enzymes, slow tumour growth
What is fulvesterant?
Pure antioestrogen
Mimics oestrogen ablation
Used as a 3rd line therapy
Describe goserelin
One amino acid changes from the LHRH peptide
Binds to receptors in pituitary initially stimulating LH/FSH release but comntinous exposure leads to thee down regulation of the receptors and decreases FSH production within 2 weeks
What is the significance of endometrial cancer in breast cancer?
Stimulates from high unopposed oestrogen levels
Usually in post menopausal women as they stop making progesterone
Tamoxifen has partial agonist properties particularly the uterus and increases the risk of endometrial cancer
How can you classify breast cancer?
Histological types of breast carcinoma:
In situ carcinoma
Invasive carcinoma- Ductal NST, lobular, tubular, medullary-like, mucinous, metaplastic
Morphological factors- size, node involvement, tumour grade
Nottingham prognostic index (NPI)- 5.41= poor
Describe luminal A breast cancer
ER, PR positive- responsive to endocrine therapy
Mostly diploid, few copy number changes, low proliferation, recurrently mutated genes (PIK3CA, CDH1, MAP3K1, MAP2KA, FOXA1, TP53, RUNX1- less responsive to chemotherapy
Describe luminal B breast cancer
ER/PR positive, lower than Luminal A, 25% HER2+- not as responsive to endocrine therapy as Luminal A
Often aneuploid with many high level focal amplifications (cyclinD6 and EGFR1)
Recurrently mutated genes PIK3CA, GATA3, PTEN, TP53- more sensitive to chemotherapy
Describe basal-like breast cancer
Triple -ve for ER, PR, HER2
High metastatic rate
Young age at presentation- motte common in African American
Associated with germline BRCA1 mutations
Describe the hereditary aspect of breast cancer
Family history most important factor
3 gens, primary sites, ages
Li Fraumeni syndrome- 80% breast cancer, young, HER+ve, adrenal cortical carcinomas, sarcomas, brain tumours
Other genes: NF1, RAD51C, PALB2, ATM, BRIP1
