CBIO 6: Hormones and Cancer Flashcards
Observe the learning outcomes of this session
Define hormone
- Hormones are naturally occurring substances produced in specific parts of our bodies and act as chemical messengers
- They travel through the blood to control functions of other tissues and organs.
Label which organ each hormone targets
(there may be more than one correct answer)
- this is a simplified diagram and there are other possibilities as well
What are the three classes of hormones?
Give some examples
- peptide/protein hormones:
- e.g. insulin
- amine hormones:
- e.g. adrenaline
- steroid hormones:
- e.g. gonadal steroids
- e.g. oestrogens and androgens
What are steroid hormones synthesised from?
How?
- all steroid hormones are synthesised from cholesterol
- the synthesis begins by intake of cholesterol into the steroid producing cells
- sources could be dietary or de novo synthesis in the liver
What are the different steroid hormones classes?
Why are they linked?
- androgens
- oestrogens
- progestins
- glucocorticoids
- mineralocorticoids
- the figure will show that all synthetic pathways of all steroids are linked, so they are likely to impact each other
What are second messengers?
- a small molecule that transfers a signal through cell surface receptors (e.g. ion-channel coupled receptors, G-protein coupled receptors, enzyme-linked receptors )
Do steroid hormones require a second messenger?
- no
- they can act directly on intracellular receptors due to their lipophilicity
Describe how steroid hormones enter cells and what they bind to inside the cell
- by being lipid-soluble, steroid hormones enter cells through the lipid-rich plasma membrane and then bind to so-called nuclear receptors
- Nuclear receptors are transcription factors that regulate gene expression and hence protein production.
- There are 48 nuclear receptors in humans.
- The subset of nuclear receptors that mediate steroid hormone signalling are steroid receptors, and examples of these include oestrogen receptors and androgen receptor.
What type of cancers are breast and prostate cancers?
- breast and prostate cancers are known as hormone-dependent cancers or endocrine cancers
How common of a UK cancer killer are breast and prostate cancers for women and men, respectively?
- they are the second most common UK cancer killer
Can hormones cause cancer?
- It is a matter of debate whether hormones can actually cause cancer, i.e. are carcinogenic, or whether the simply increasing the risk of cancer occurring due to them causing increased proliferation of cells.
- Although hormones have essential physiological roles in both females and males, their pharmaceutical use has been linked to various cancers.
- Using combined menopausal hormone therapy (oestrogen plus progestin) can slightly increase a woman’s risk of breast cancer, while oestrogen-only therapy slightly increases the risk of endometrial cancer and is only used in women who have had a hysterectomy (surgery to remove a woman’s uterus or womb).
- Diethylstilbestrol (DES) is a synthetic oestrogen that was given to some pregnant women in the 1940s-70s to prevent miscarriages, premature labour, and related pregnancy problems.
- This was discontinued when it became apparent that women who took DES had increased risk of breast cancer and their daughters have increased risk of a vaginal or cervical cancer.
- Possible effects on the grandchildren are still being studied.
- Increased breast cancer risk is associated with early onset of puberty, late menopause and late or no first pregnancy, all factors that increase exposure to oestrogen cycles.
- Other hormones including insulin have been associated with higher risks of pancreatic, liver, kidney, stomach and respiratory cancers, and insulin-like growth factors (IGFs) with prostate, breast and bowel cancers.
What are the key differences between oestrogens and androgens?
- Oestrogens (e.g. oestradiol/estradiol) are produced in ovaries and are required for development of female secondary sex characteristics.
- Androgens (e.g. testosterone) are mainly produced by the testes and are responsible for the development of male secondary sex characteristics.
- However, note that males and females each have both androgens and oestrogens – it is the ratio that is different.
How are oestrogen and androgen production regulated?
- their production is regulated by luteinising hormone (LH)
- which is produced by the anterior pituitary gland
- LH secretion is in turn regulated by gonadotrophin-releasing hormone (GnRH)
Describe this diagram of androgen and oestrogen production in more detail
- GnRH, from the hypothalamus, interacts with its receptor in the anterior pituitary to stimulate the production of LH/FSH
- LH stimulates testosterone production from the interstitial cells of the testis;
- FSH stimulates oestrogen production from the ovary (FSH and LH have additional roles in the testis and ovary also).
- The circulating hormones in the blood feedback on both the hypothalamus and pituitary to negatively regulate their own production.
- note that androgens are also produced in the adrenal gland
- Adrenal androgens include DHEA and androstenedione
What is androstenedione converted to in females?
What is this process called?
- In females, androstenedione is converted to oestrogens:
- oestrone
- 17ß-oestradiol (E2): the key circulating oestrogen hormone during reproductive years
- oestriol: predominant during pregnancy and oestrone during menopause.
- this process is called aromatisation and oxidation
What other androgen can oestradiol be synthesised directly from?
- testosterone
How do testosterone and oestrogens autoregulate their levels?
- Testosterone and oestrogens feed back negatively on pituitary LH and hypothalamic GnRH to autoregulate the levels of these and in consequence their own levels.
Where do oestrogen receptors (ERs) and androgen receptors (ARs) bind?
In what form do they bind?
- ERs and ARs bind as homodimers
- this means a pair of the same molecule
- they bind to specific DNA sites, known as response elements
What are the nucleotide sequences of:
- oestrogen response elements (EREs)
- androgen response elements (AREs)?
- These consist of two 6-nucleotide sequences (which can vary slightly in sequence) separated by 3 unconserved nucleotides (represented by n below):
- oestrogen response elements (EREs): 5’-(A/G)GGTCAnnnTGACC(T/C)-3’
- androgen response elements (AREs): 5’-GG(A/T)ACAnnnTGTTCT-3’
What are the two oestrogen receptors?
Which genes encode for them?
- ERα: encoded by ESR1 gene
- ERβ: encoded by ESR2 gene
Describe the structure of the oestrogen receptor ligand-binding domain (plus ligand in grey)
- As you can see, the ligand-binding domain has a lot of helical structure (the pink and white ribbon-like structures)
- and the ligand (oestradiol) is snugly tucked into a pocket formed by these helices.
What are the three main functional domains of ERs and AR?
- N-terminal transcriptional regulation domain (contains activation function AF-1)
- DNA-binding domain (DBD)
- Ligand-binding domain (LBD, contains AF2).
What is the nuclear localisation signal (NLS) in ERs and AR?
Where is it?
What is its function?
- Between the DNA- and ligand-binding domains is a nuclear localization signal (NLS) which promotes translocation of the ligand-receptor complex into the nucleus.
- This becomes exposed when ligand binds to the receptor.
How do ERs and AR bind to EREs and AREs, respectively?
Where in the cell does this occur?
What determines this?
- both ERs and AR require ligand binding and dimerization to bind to EREs and AREs, respectively
- this occurs in the nucleus
- their activity is determined by coregulators which either enhance (co-activator) or inhibit (co-repressor) their ability to transactivate the target gene
Observe this diagram and describe co-regulator complexes and ERs and AR bind to EREs and AREs
- Once inside the nucleus, ERα interacts with EREs where it recruits co-regulator complexes.
- These first coactivators, the example shown here is p160, recruit further coactivators, here shown as CREB binding protein (CBP)/p300, which has intrinsic histone acetyltransferase (HAT) activity.
- This results in acetylation of histones near to the ERE, which causes opening up of the chromatin which in turn facilitates recruitment of RNA polymerase II (PolII) to initiate transcription.
- PolII itself is then phosphorylated by coactivators, resulting in an elongation-competent form.
What type of glands are breast and prostate?
- exocrine glands
What is the difference between an exocrine and endocrine gland?
- an exocrine gland secretes substances to the outside of the body via one or more ducts
- an endocrine gland secretes substances that are retained in the body
- normally these substances (e.g. hormones) are secreted directly into the blood
Look at this diagram and describe where 90% of breast and prostate cancers arise?
- the secretory cells that line the duct is the luminal epithelial cell layer and 90% of breast and prostate cancers arise
Where do the breast and prostate secrete outside?
How?
- breast and prostate contain many such glands (what glands), joined in a branching structure
- they secrete to the outside via the nipple and the urethra, respectively
Are ERα and ERβ expressed differently in males and females?
Why?
- ERα and ERβ are both found in males and females, though the expression pattern is different (summarised below) as they play different roles.
- There is evidence that when they are present in the same cells the action of ERβ can actually oppose that of ERα.
Summarise the functions of ERα and ERβ
Describe some statistics for breast cancer
- 1 in 8 women will be diagnosed with breast cancer at some point in their life
- 31% of cancers diagnosed in women are breast cancer, making it the most common cancer in women.
- 1 in 5 cases of breast cancer are in women under 50.
What are the key events in breast cancer progression?
- ductal hyperproliferation
- evolution into carcinoma in situ
- invasive carcinoma
- metastatic disease
What are the risk factors of breast cancer?
- Age: 4 in 5 cases of breast cancer are in women above 50
- Family history: one first-degree female relative (mother or sister) diagnosed with breast cancer doubles the risk
- Genetics: 5-10% of breast cancers are thought to be hereditary
- Radiation exposure: radiation to chest or face before age of 30 increases the risk
- Being overweight
- Early menstruation (before age of 12)
- Hormone replacement therapy
What are the symptoms of breast cancer?
- New lump or mass in breast tissue
- Swelling of all or part of a breast
- Skin irritation or dimpling
- Breast or nipple pain
- Nipple retraction
- Nipple discharge (other than breast milk)
- Redness, flaking, or thickening of the nipple or breast tissue
Describe the structure of normal breast ducts
What is their function?
- composed of:
- basement membrane
- a layer of luminal epithelial cells
- a layer of basal epithelial (myoepithelial) cells
- its function is to secrete milk
What causes breast ducts to become cancerous?
Describe its progression
- transforming events (genetic and epigenetic) in a single cell result in uncontrolled proliferation of the transformed cells
- causing ductal (in ducts) or lobular (in lobules) hyperplasia (enlargement of tissue due to increased cell division)
- The atypical breast hyperplasia is followed by ductal carcinoma in situ (this translates as “in the original place”) and invasive ductal carcinoma regulated by genetic and epigenetic alterations.
- The final stage is metastatic disease.
What does it mean by ‘breast cancer is a heterogenous disease’?
- it has several root causes
- involving a variety of pathological features
What percentage of breast cancers are ERα-positive?
Is ERβ usually expressed?
- 70-80% of breast cancers are ERα-positive
- ERβ is also usually expressed but its levels are often decreased in tumour cells.