Hormones and Cancer Flashcards
Define hormones and describe the different classes
Hormones are naturally occuring chemicals produced by the body to act as chemical messengers, travelling through the blood to act on target organs and tissues. They’re divided into 3 classes: peptide (insulin), amine (adrenaline), steroid (testosterone).
Describe the synthesis of steroid hormones
All steroid hormones are synthesised from cholesterol. Cholesterol is taken into the steroid producing cells, where it is synthesised into the different steroid hormone classes: androgens, oestrogens, progestins, glucocorticoids, mineralocorticoids. The steroid synthesis pathways are all likely linked.
Explain the signalling pathway for steroid hormones
Steroid hormones, due to their lipophilicity, can cross the lipid bilayer and interact with intracellular receptors. These nuclear receptors (not neccessarily in the nucleus) are TFs, and there’s 48 of them in humans.
Which cancers are regulated by hormones?
Prostate and breast cancers are hormone dependent or endocrine cancers
How can different hormones affect a woman’s risk of getting breast cancer?
Combined menopausal hormonal therapy (oestrogen and progestin) can slightly increase a woman’s risk of breast cancer, but oestrogen only therapy can increase risk of endometrial cancer and is only used in women that have had a hysterectomy
How can oestrogen affect pregnant women?
Diethylstilbestrol is a synthetic oestrogen that was given to some pregnant women in 40s-70s to prevent miscarriages, premature labour, and related pregnancy problems. It was discontinued when it was out found that women taking DES had increased risk of breast cancer and daughters had increased vaginal and cervical cancer risk. The effects on grandchildren are still being studied.
In which other ways are hormones associated with increased cancer risk?
Increased BC risk associated with early onset puberty, late menopause, late or no first pregnancy - these factors all result in increased exposure to the oestrogen cycle. Other hormones, like insulin, have been associated with increased risk of pancreatic, liver, kidney, stomach, respiratory cancers. Insulin-like GFs are associated with bowel, prostate, and breast cancers.
Describe the properties of oestrogens and androgens
Oestrogens eg. Oestradiol are produced by the ovaries and are required for the development of female sex characteristics. Androgens eg. Testosterone are produced by the testes and are required for the development of male sex characteristics. Both sexes require both but in different quantities
Describe the synthetic pathways of oestrogens and androgens
The production of both hormones is controlled by LH, which is produced by the anterior pituitary. LH production is regulated by the release of gonadotropin-releasing hormone. Adrenal gland produces DHEA and androstenedione. In females, androstenedione is turned into oestrone, 17B oestradiol (E2), and oestriol. E2 is the key circulating hormone in reproductive years, oestriol in pregnancy, oestrone in menopause. The conversion involves aromatisation and oxidation. Oestradiol can be synthesised directly from testosterone.
How do ERs and ARs carry out their TF function
They bind as homodimers to specific DNA sequences known as response elements - the structure of which is 2 6nt sequences separated by 3 unconserved nucleotides.
Describe the structure of the ER and AR receptors
There are 3 main functional domains, the Ligand Binding domain (containing activation factor II), N terminal transcription regulating domain (contains AFI), and the DNA binding domain. When the ligand binds, the nuclear translocation signal is exposed which promotes translocation of the complex to the nucleus.
Describe the nuclear signalling pathway of steroid receptors
Once E/ARs bind to E/AREs, their activity is regulated by coregulators. On interaction with the RE, coregulators are recruited that either activate or inhibit activity. The first coactivator (P100) recruits more (CREB BP) which has intrinsic histone acetyltransferase activity. This result in histone acetylation near the RE, resulting in opening up of the chromatin, so RNA Pol II can initiate transcription. The coactivators phosphorylate RNA Pol II so it’s elongation competent
Describe the similarities between the breast and the prostate
They are both exocrine glands, in that they secrete substances outside the body, via ducts. 90% of breast and prostate cancers are in the luminal epithelial cell layer. The breast and prostate contain many exocrine glands, joined in a branching structure.
Describe the difference in action of each type of oestrogen receptor, ERa and ERb
The expression pattern of each receptors differs in both males and females, and this expression is what results in different roles in both males and females. Also, when present in the same cells, ERa activity can oppose ERb activity.
Outline the key events in breast cancer progression
Ductal hyperproliferation, evolution into carcinoma in situ, invasive carcinoma, and metastatic disease
Outline risk factors for breast cancer
Age - 80% of cases over 50 Family history - Mum or sis diagnosed = 2x risk Genetics - 5-10% cases probs hereditary Radiation exposure Overweight Menstruation before 12 Hormone Replacement Therapy
Describe the pathology of breast cancer
Normal breast ducts (secrete milk) and are composed of basement membrane, with a layer of luminal epithelia and basal epithelia. Transforming events (genetic or epigenetic) in one cell lead to uncontrollable proliferation which leads to ductal or lobular hyperplasia.
Explain the different classifications of breast cancer
70-80% of cancers are ERa+, a hallmark of hormone dependent cancer growth. ERb expression is often decreased in tumour cells.
Subclassification of invasive ductal carcinoma involves expression levels of ER, progesterone receptor (ER target gene, ER activity marker), and HER2. Further classification involves expression of a related GF receptor (HER1), and various cytokeratins.
ER- cancers are HER2+ (enriched) or triple negative (basal-like and low claudin subtypes). Classification gives an idea of prognosis and sometimes best treatment course
Explain the different subclassifications of ER+ breast cancer
All ER+ cancers are luminal, subdivided into HER2+ (enriched, Luminal B) and HER2- (luminal A).
Describe and explain the role that genes play in breast cancer development
Tumour suppressor genes involved in familial breast cancer:
BRCA1/2 - DNA repair and cell death, mutations account for 10% of cases
ATM - DNA repair. Underlies ataxia-telangiectasia (autosomal recessive), a disease where sufferers have x100 cancer risk
BARD1 - Associates with BRCA1, regulating apoptosis
How can breast cancer be detected?
Mammography, MRI, biopsy. The treatment success is monitored by these methods also.
Describe the treatments for breast cancer
Ovariectomy (to reduce ovarian function - oestrogen production). Synthetic steroidal and non steroidal oestrogens, oestrogen antagonists (anti-oestrogens), non ER-modulating drugs (Aromatase inhibitors)
Describe how SERM/SERDs work
Selective ER modulators/downregulators. Tamoxifen/Fulvestrant.
SERMs act as antagonists in mammary tissue, stimulating cholesterol metabolism, bone density, and cell prolif in endometrium. Induces conformational change in ER.
SERD inhibits ER dimerisation and accelerates ER degredation and reduced expression
