Hormone-Driven Cancers Flashcards
List 7 risk factors for breast cancer.
1 - Age.
2 - Oestrogen exposure (early menarche of <12 years, late menopause of >52 years and lack of child bearing).
3 - Previous breast disease.
4 - Family history (especially when associated with the BRCA gene).
5 - Alcohol.
6 - Smoking.
7 - Radiation.
Why might an ovarian ablation be carried out?
List 2 ways by which ovarian ablation can be carried out.
- An ovarian ablation might be carried out as a form of therapy for premenopausal women suffering from breast cancer, as it will reduce oestrogen release.
1 - Surgically if the cancer is related to the BRCA gene.
2 - Chemically via GnRH analogues, e.g. Goserelin.
List the molecular subtypes of breast cancer.
Which of these subtypes are suitable for endocrine-targeted therapies? Why?
*There are also histological types which are covered in the breast cancer lecture.
Molecular subtypes of breast cancer include:
1 - Luminal A.
2 - Luminal B.
3 - HER2 receptor-positive breast cancer.
4 - Triple-negative breast cancer (no involvement of oestrogen receptors, HER2 receptors or progesterone receptors).
- Luminal A and B are associated with oestrogen receptor expression and are therefore suitable for endocrine-targeted therapies.
How do oral contraceptives affect risk of developing breast cancer?
- There is only an increase in risk of developing breast cancer if oral contraceptives are taken before the age of 20.
- The risk is reversed when the contraceptives are no longer taken.
How does the oestrogen receptor work to influence gene transcription?
- There are two forms of the receptor - alpha and beta.
- The receptor has two functional domains (but 5 domains overall) - a ligand-binding domain and a DNA-binding domain.
- It is present in the nucleus, where it is bound the HSP90, which regulates the receptor.
- Binding of the receptor to oestrogen causes dimerisation and phosphorylation of the receptor. This causes HSP90 to dissociate.
- This allows the receptor to bind to coactivators and release corepressors, which results in the exposure of transcriptional activator factor regions (TAF1 & 2).
- This allows the receptor to bind to DNA via TAF1 & 2, resulting in an increase in gene transcription.
List the genes that are affected by the oestrogen receptor.
How can this result in breast cancer?
1 - Progesterone receptor (PR).
2 - Insulin-like growth factor (IGF).
3 - TGF-alpha.
- These factors stimulate cell growth, and also bind back onto receptors that increase their transcription in an autocrine positive feedback loop.
List 3 hormone therapy treatments for breast cancer.
1 - GnRH-releasing hormone analogue (only for premenopausal).
2 - Aromatase inhibitors (for postmenopausal).
3 - Selective oestrogen receptor modulators (SERM), e.g. tamoxifen.
List 3 situations in which chemotherapy is used instead of hormone therapy to treat breast cancer.
Chemotherapy is used instead of hormone therapy if:
1 - The tumour is poorly differentiated.
2 - There is lymph node involvement.
3 - The tumour is oestrogen receptor-negative.
Describe the mechanism of action of tamoxifen.
- Tamoxifen is a competitive inhibitor of the binding of oestrogen to the oestrogen receptor.
- Binding of tamoxifen to the oestrogen receptor means that the oestrogen receptor cannot dissociate form HSP90, bind to coactivators, release corepressors and expose binding sites.
- There is therefore no increase in transcription of growth factors.
- Although tamoxifen causes TAF2 to remain unexposed, TAF1 is still activated. This isn’t a problem for breast cancer.
List 3 cellular changes that occur over time with tamoxifen use.
Prolonged tamoxifen use might cause:
1 - Tamoxifen resistance (many proposed mechanisms).
2 - Upregulation of heregulin receptors.
3 - Upregulation of EGF receptors.
- In this case, MAPK (from the EGF and heregulin receptors) causes phosphorylation of the oestrogen receptor instead of oestrogen - the oestrogen receptor is still being activated.
Describe the mechanism of action of aromatase inhibitors for the treatment of breast cancer in postmenopausal women.
- In postmenopausal women, oestrogen is mainly controlled by the conversion of testosterone to oestradiol in adipose tissue and the adrenal glands by aromatase (not by the ovaries, which is the main regulator of oestrogen in premenopausal women).
- Inhibiting aromatase will therefore decrease oestrogen production.
Describe the mechanism of action of goserelin.
- Goserelin binds to GnRH receptors in the pituitary.
- Initially, this stimulates FSH and LH release. *This is counterintuitive because FSH and LH stimulate oestrogen release.
- However, continuous exposure (over 2 weeks) causes downregulation of GnRH receptors, lowering FSH production. This reduces oestrogen release.
List 4 risk factors for endometrial cancer.
1 - Oestrogen exposure (early menarche of <12 years, late menopause of >52 years and lack of child bearing).
2 - PCOS.
3 - Bleeding after menopause.
4 - Irregular menstruation.
What is the effect of HRT on breast and endometrial cancer?
HRT increases the risk of both breast and endometrial cancer.
Why does tamoxifen increase risk of endometrial cancer?
Tmaoxifen increase risk of endometrial cancer due to its partial agonist properties due to partial activation of the TAF1 region of the oestrogen receptor.
