CBIO 6: Hormones and Cancer Flashcards
1
Q
Observe the learning outcomes of this session
A
2
Q
Define hormone
A
- 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.
3
Q
Label which organ each hormone targets
(there may be more than one correct answer)
A
- this is a simplified diagram and there are other possibilities as well
4
Q
What are the three classes of hormones?
Give some examples
A
- peptide/protein hormones:
- e.g. insulin
- amine hormones:
- e.g. adrenaline
- steroid hormones:
- e.g. gonadal steroids
- e.g. oestrogens and androgens
5
Q
What are steroid hormones synthesised from?
How?
A
- 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
6
Q
What are the different steroid hormones classes?
Why are they linked?
A
- 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
7
Q
What are second messengers?
A
- a small molecule that transfers a signal through cell surface receptors (e.g. ion-channel coupled receptors, G-protein coupled receptors, enzyme-linked receptors )
8
Q
Do steroid hormones require a second messenger?
A
- no
- they can act directly on intracellular receptors due to their lipophilicity
9
Q
Describe how steroid hormones enter cells and what they bind to inside the cell
A
- 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.
10
Q
What type of cancers are breast and prostate cancers?
A
- breast and prostate cancers are known as hormone-dependent cancers or endocrine cancers
11
Q
How common of a UK cancer killer are breast and prostate cancers for women and men, respectively?
A
- they are the second most common UK cancer killer
12
Q
Can hormones cause cancer?
A
- 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.
13
Q
What are the key differences between oestrogens and androgens?
A
- 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.
14
Q
How are oestrogen and androgen production regulated?
A
- 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)
15
Q
Describe this diagram of androgen and oestrogen production in more detail
A
- 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
16
Q
What is androstenedione converted to in females?
What is this process called?
A
- 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
17
Q
What other androgen can oestradiol be synthesised directly from?
A
- testosterone
18
Q
How do testosterone and oestrogens autoregulate their levels?
A
- Testosterone and oestrogens feed back negatively on pituitary LH and hypothalamic GnRH to autoregulate the levels of these and in consequence their own levels.
19
Q
Where do oestrogen receptors (ERs) and androgen receptors (ARs) bind?
In what form do they bind?
A
- ERs and ARs bind as homodimers
- this means a pair of the same molecule
- they bind to specific DNA sites, known as response elements
20
Q
What are the nucleotide sequences of:
- oestrogen response elements (EREs)
- androgen response elements (AREs)?
A
- 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’
21
Q
What are the two oestrogen receptors?
Which genes encode for them?
A
- ERα: encoded by ESR1 gene
- ERβ: encoded by ESR2 gene
22
Q
Describe the structure of the oestrogen receptor ligand-binding domain (plus ligand in grey)
A
- 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.
23
Q
What are the three main functional domains of ERs and AR?
A
- N-terminal transcriptional regulation domain (contains activation function AF-1)
- DNA-binding domain (DBD)
- Ligand-binding domain (LBD, contains AF2).
24
Q
What is the nuclear localisation signal (NLS) in ERs and AR?
Where is it?
What is its function?
A
- 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.
25
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
26
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.
27
What type of glands are breast and prostate?
- exocrine glands
28
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
29
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
30
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
31
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.
32
Summarise the functions of ERα and ERβ
33
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.
34
What are the key events in breast cancer progression?
- ductal hyperproliferation
- evolution into carcinoma *in situ*
- invasive carcinoma
- metastatic disease
35
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
36
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
37
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
38
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.
39
What does it mean by 'breast cancer is a heterogenous disease'?
- it has several root causes
- involving a variety of pathological features
40
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.
41
What is Erα expression a hallmark of?
- it is a hallmark of hormone-dependent tumour growth
42
Describe the histopathological subclassification of invasive ductal carcinoma
- The histopathological subclassification of invasive ductal carcinoma includes expression levels of:
- ER
- progesterone receptor (PR), which is a target gene of ER
- so a marker of ER activity
- human epidermal growth factor receptor 2 (HER2)
- Further classification includes expression of a related growth factor receptor, HER1 (also known as EGFR or ErbB1), and various cytokeratins.
- All ER+ breast cancers are classified as luminal cancers, which are further subdivided into:
- HER2+ (HER2-enriched, luminal B)
- or HER2- (luminal A). ER- breast cancers are subdivided into HER2+ (HER2-enriched) or triple-negative (basal-like and claudin-low subtypes).
- This classification helps give some indication of the likely prognosis and, in some cases, the best treatment for the patient.
43
Describe HER2
Its role in breast cancer
Describe the gene encoding it
- HER2 is a member of the human epidermal growth factor receptor family, which also includes EGFR (HER1), HER3, and HER4.
- In breast cancer, HER2 behaves as an oncogene through overexpression.
- It is encoded by gene *ERBB2.*
44
What are the tumour suppressor genes in which inherited mutations are associated with breast cancer?
- *BRCA1* and *BRCA2*:
- key role in DNA repair and cell cycle
- mutations account for up to 10% familial breast cancers.
- *ATM*:
- gene underlying the autosomal recessive condition ataxia-telangiectasia (also known as Louis–Bar syndrome)
- individuals with this condition have a 100-fold increased risk of cancer.
- Again, involved in DNA repair.
- *BARD1*:
- interacts with BRCA1, regulates cell apoptosis
45
How are breast cancers detected and screened for?
- screening:
- mammography
- MRI
- diagnostics:
- biopsy
46
Describe the history of ER+ breast cancer treatment
- the role of oestrogen in breast cancer progression was first noted in 1889 by Albert Schinzinger who noticed breast atrophy after ovarian function had ceased due to menopause.
- He proposed oophorectomy (surgical removal of ovary/ies, also termed ovariectomy) to treat breast cancer.
- In 1896, George Beatson reported that bilateral oophorectomy in pre-menopausal women resulted in disease regression and improved prognosis.
- In 1923, ovarian oestrogen was purified by Allen and Doisy, and in the 1930s, oestrogens were shown to promote mammary tumour formation.
- Since then, various drugs modulating the functions of oestrogen receptor have been developed, including synthetic steroidal and nonsteroidal oestrogens, anti-oestrogens (oestrogen antagonists/blockers, see table below) and also non-ER-modulating drugs (e.g. aromatase inhibitors).
47
See the table for some anti-oestrogens
48
What is a current treatment for ER+ disease?
- premenopausal women
- postmenopausal women
- Currently all patients with ER-positive disease receive long-term antihormonal therapies.
- In premenopausal women, this is usually tamoxifen, sometimes with the addition of GnRH superagonists, which counterintuitively inhibit the hypothalamic/pituitary axis-regulated production of oestrogen
- In premenopausal women, the major source of oestrogen is from ovarian production, which is why GnRH agonists are used to inhibit this.
- However, in postmenopausal women, the majority of oestrogen is generated from hormonal precursors (androgens) largely produced by the adrenal glands.
- The oestrogen is made peripherally in tissues such as adipose.
49
In a previous section you’ve learnt about the synthesis of oestrogens. Do you remember what was driving the conversion of androstenedione to oestrogens?
- Aromatisation (of the ‘A’ ring) of testosterone and androstenedione is the final step in the production of oestrogens.
50
How do aromatase inhibitors (AIs) treat breast cancer?
Who do they treat?
- Aromatase inhibitors (AIs) are used to inhibit aromatase (an enzyme in the endoplasmic reticulum of oestrogen-producing cells), to block conversion of testosterone to oestrogens.
- AIs are used to treat breast cancer in postmenopausal women and include type I steroidal inhibitors (e.g. exemestane) and type II non-steroidal inhibitors (e.g. anastrozole and letrozole).
- The type I AIs act as irreversible suicide inhibitors. Type II agents act reversibly, binding with the haem group of aromatase.
- AIs inhibit oestrogen production in all tissues.
51
What are the two modes of tamoxifen resistance?
- intrinsic:
- either ER+ or ER- tumour cells with pre-existing enhanced survival pathways
- acquired:
- ER+ tumour initially responds to tamoxifen but later becomes resistant through clonal selection of tamoxifen-resistant cells
52
Describe some breast cancer resistance mechanisms
a) Coactivators and corepressors:
- Changes in levels of ER coactivators/corepressors can alter the activity of ER.
- For example, overexpression of the ER coactivator AIB1 is associated with clinical and experimental tamoxifen resistance, while downregulation of the corepressor NCoR occurs in tamoxifen-refractory tumours (in laboratory models).
- This phenomenon is also seen in prostate cancer and is explained in more detail in that section.
b) Growth factor signalling
- Growth factor signalling pathways, like HER2 or MAPK, can provide alternative proliferation and survival stimuli to breast cancer cells in the presence of ER inhibitors.
- They can also cause therapy resistance by modulating ER and increasing its activity (sometimes entirely independent of ER ligand).
- These pathways can be activated by overexpression of the receptors or their cognate ligands.
- Pathway activation can also occur through deregulation of downstream signalling molecules (example: activating mutation in PI3K or loss of expression of PTEN tumour suppressor).
c) Androgen receptor
- It appears that ER activity can in some cases be substituted by other nuclear receptors, like androgen receptor (AR)
- AR is expressed in 80-90% of ER+ breast cancers, and in the absence of ER, AR may initiate cell division.
d) ER mutation
- During treatment, cancer cells acquire further mutations.
- Acquired mutations in ESR1, the gene encoding ERα, was first reported in 1997.
- These mutations can result in increased or even constitutive activation of the ER even in the absence of oestradiol.
53
Can you compare the intrinsic and acquired resistance, and list other mechanisms of hormone resistance?
- In intrinsic resistance, cells have pre-existing enhanced survival pathways, while in acquired resistance, cells initially respond and later become resistant through clonal selection.
- These mechanisms of resistance include changes in coactivators and corepressors, involvement of growth factor signalling, ER substitution with androgen receptor and genetic polymorphism.
54
What key roles in the development of the prostate do androgens play?
they control:
- Growth during embryonic/neonatal stage (initiated by androgen surge, requires androgens and growth factors)
- Growth at puberty
- Secretory function during adult life (maintained by high levels of androgens)
- And unfortunately....Second growth spurt (aberrant, breakdown in regulation)
55
Describe how androgens determine male sexual differentiation in the embryo
- In male embryos, the Müllerian duct system regresses and the Wolffian ducts are stabilised by androgens
- The latter process is regulated by testosterone, synthesised from around 9 weeks by the Leydig cells of the fetal testis. In this process, the prostate and the prostatic utricle (see below) are formed.
- In some target organs, testosterone is converted to a more potent androgen, dihydrotestosterone (DHT).
- It is DHT that drives prostate development as well as masculinisation (virilisation) of the external genitalia.
56
What is the Mullerian and Wolffian duct?
- Mullerian duct: the precursor of the female internal reproductive system
- Wolffian duct: the precursor of the male internal reproductive system.
57
What is the prostatic utricle?
- a remnant of Mullerian duct and forms an indentation in the prostatic urethra.
58
Where is the prostate located?
What is its size?
- The prostate gland is a walnut sized organ at the base of the bladder, encircling the urethra
59
What are the major morbidities associated with the prostate gland?
- benign prostatic hyperplasia (BPH)
- prostate cancer
- prostatitis (the inflammation of the prostate gland)
60
Describe the structure of a prostate epithelium
- In mature prostate epithelium, luminal epithelial cells (tall, columnar cells lining the duct) express
- cytokeratins 8 and 18
- secretory proteins (like PSA, see later)
- high levels of androgen receptor (AR)
- while non-secretory basal epithelial/myoepithelial cells express
- cytokeratins 5, 14
- p63
- no/very little AR.
- Within the basal cell layer are rare neuroendocrine cells secreting neuropeptides and other hormones
- The stromal compartment consists of
- smooth muscle cells
- mature fibroblasts that secrete extracellular matrix
- blood vessels
- lymphatics
- nerves
- immune cells.
61
Explain how to differentiate between basal and luminal epithelial cells?
- Both epithelial cell types express surface markers that are specific to them, those are called cytokeratins
- Basal cells express keratin 5 and 14, while luminal cells keratin 8 and 18.
62
What is prostatic fluid?
- The prostate secretes an alkaline fluid that aids in sperm survival.
- Components of prostatic fluid include zinc, citrate, coagulative enzymes, prostate specific antigen (PSA) and other proteases, and polyamines.
63
What are some statistics of prostate cancer?
- 1 in 8 men will develop prostate cancer at some point in their lives in the UK.
- Over 50: Prostate cancer mainly affects men over 50 and the risk increases with age.
- 65-69: The average age for men to be diagnosed with prostate cancer is between 65 and 69 years.
- Prostate cancer is the most commonly diagnosed cancer in men in the UK, and the second biggest cancer killer.
64
What are the risk factors for prostate cancer?
- Age: at the age of 50 years, around 40% of men have foci of prostate cancer and by 80 years, 70% of men will have prostate cancer detectable on biopsy.
- (Bear in mind many are not and will not become clinically significant, the 1 in 8 statistic refers to clinically significant disease).
- Over 90% of those diagnosed with prostate cancer are over the age of 60.
- The median age of diagnosis is 72.
- Race/ethnicity: more common in north-western Europe, North America, Australia, less common in Asia, Africa, Central and South America
- Family history: inherited or genetic factors, for instance inherited mutations of BRCA1 or BRCA2
- Hormone levels in utero may affect prostate cancer risk
65
What are the symptoms of prostate cancer?
- Frequent trips to urinate
- Poor urinary stream
- Urgent need to urinate
- Hesitancy whilst urinating
- Lower back pain
- Blood in the urine
- However, sometimes it is asymptomatic (no noticeable symptoms)
66
Label this diagram of a prostate gland
67
Where layer do 90% of prostate adenocarcinomas arise in?
- 90% of prostate adenocarcinomas arise in the luminal epithelial cells
- while the basal epithelial cell layer is absent in most tumours.
68
Describe the multistep malignant process for the normal prostate epithelium
- initiating prostatic intraepithelial neoplasia (PIN)
- followed by localized prostate cancer and invasive adenocarcinoma
- culminating in castration-resistance and metastasis (usually to the lymph nodes and bone, less frequently liver, lung, brain)
- The stroma is altered to become supportive of the tumour growth.
69
Describe the Gleason grading system used to classify prostate tumours
- The classic histopathological Gleason grading system is used to classify prostate tumours based on comparative tissue architecture.
- Here grade 1 indicates morphology similar to normal tissue (well-defined ducts and epithelial layers), while grade 5 cancer looks very abnormal (ducts are largely lost, sheets of epithelial cells predominate).
- Prostate cancer often has areas of different grades, so a grade is assigned to each of the 2 areas that constitute most of the cancer,
- e.g. a tumour may be described as “Gleason 4+3”.
70
Is prostate cancer susceptibility heritable?
- having a first-degree relative with the disease doubles the chances of getting it yourself.
- However, unlike breast cancer, we haven’t found one gene that can account for a significant proportion of familial cases.
- Instead, a large number of genes are associated each with a relatively small percentage of cases.
71
What are the most commonly associated mutations in prostate cancer?
* - PTEN:*
- tumour suppressor gene, lost in breast and prostate cancer,
- loss causes Cowden disease (predisposition to many tumours), encodes a protein tyrosine phosphatase which inactivates anti-apoptotic proteins (e.g. Akt).
- Effect on AR activity is controversial
* - BRCA2:*
- may account for 5% of cases of familial prostate cance
- relative risk of prostate cancer if carrying BRCA2 mutation = 4.7
- relative risk of getting it below age 65 if carrying BRCA2 mutation = 7.3
* - ETS fusions*:
- the most common prostate cancer genomic alterations are translocations between androgen-regulated promoters and the ETS family of transcription factors.
- This results in androgen-driven expression of the (oncogenic) ETS factor.
- *NKX3.1*:
- an androgen-regulated homeobox gene, which is frequently deleted in prostate cancer.
- Its haploinsufficiency (see below) is an initiating event in prostate carcinogenesis
- *MYC:*
- its overexpression is observed even at the PIN stage, and it can drive progression to invasive adenocarcinoma, genomic instability and metastasis
72
What is haploinsufficiency?
- where loss of one copy of a gene is enough to cause a phenotype
73
What are some ways to detect prostate cancer?
- Digital rectal examination (DRE)
- PSA test (blood sample, antibody-based assay
- Ultrasound – to detect tumour outside prostate capsule
74
Why is PSA a marker for prostate cancer?
What are its functions?
- PSA is secreted by the epithelial cells and usually remains within the duct due to tight junctions between luminal cells, the basal cell layer and basement membrane.
- Any disruption in the barrier, like cell invasion or mechanical disruption, allows PSA “escape” into the stroma (which contains blood vessels) and its subsequent increased level in blood serum.
- The main biological function of PSA is to keep seminal vesicles clear by lysing seminal coagulate, which forms after ejaculation.
- PSA can also cleave other substrates giving it a putative role in prostate cancer, and possible antiangiogenic activity.
- Production of PSA is regulated by androgens, and there are several androgen response elements (AREs) in the gene promoter/enhancer regions.
75
Describe the PSA serum test
- The PSA serum test for prostate cancer was introduced in 1994.
- The normal serum levels of this protein are below 4 ng/ml, and 4 ng/ml or higher is taken to indicate possible carcinoma.
- Values can exceed 100,000 ng/ml in advanced disease.
- After diagnosis, PSA levels correlate with disease stage and treatment success.
- However, raised PSA is only an indication and a positive result always requires a biopsy for definitive diagnosis.
- Other disadvantages of the PSA test include only 70% accuracy in detection and high rates of false positives and false negatives.
76
What is a central feature of prostate cancer?
- its hormone responsiveness
- first recognized by Huggins and Hodges in 1941 (see below)
- They saw that castration led to tumour regression in prostate cancer patients.
77
What is the standard of care for inoperable prostate cancer?
- androgen-deprivation therapy (ADT)
78
Describe the different approaches the androgen pathway can be blocked for androgen-deprivation therapy (ADT) for prostate cancer
1. Testicular ablation (castration)
2. Pituitary down-regulation (chemical castration)
3. Anti-androgens: acting via several different mechanisms
4. Androgen synthesis inhibitors
79
Describe pituitary down-regulation that allows the androgen pathway to be blocked for androgen-deprivation therapy (ADT) for prostate cancer
- Example of pituitary downregulators are goserelin acetate, buserelin, leuprolide acetate
- These are usually synthetic gonadotropin-releasing hormone (GnRH) analogues analogue (or "superagonists")
- They cause an initial rise in LH and testosterone produced by the testes → the expected gonadal response to increased GnRH
- After 2 weeks, production of LH and testosterone is inhibited, due to inhibition of the pituitary-gonadal axis (we'll discuss this in the F2F).
- But DHT in the prostate is only reduced by around half, due to conversion of adrenally-produced androgens.
80
Describe anti-androgens that allows the androgen pathway to be blocked for androgen-deprivation therapy (ADT) for prostate cancer
- The original anti-androgens had steroidal structures (e.g. cyproterone acetate, CPA).
- More recently developed anti androgens are non-steroidal (e.g. enzalutamide)
- In current clinical use: commonly Bicalutamide, Enzalutamide, and Apolutamide and Darolutamide have been recently licensed for use in some situations
- They can compete with endogenous androgens for binding to the AR
- They induce a different conformational change in AR, which can lead to reduced nuclear translocation, DNA binding and coactivator recruitment → partial agonist or full antagonist function
- Some also promote recruitment of corepressors to the ARE – see below
- Some have partial antagonist/partial agonist activity (they are not completely inhibitory in all cells)
81
Describe androgen synthesis inhibitors that allows the androgen pathway to be blocked for androgen-deprivation therapy (ADT) for prostate cancer
- Inhibit one or more of the enzymatic steps leading to steroid production
- The most widely used is Abiraterone, which inhibits an enzyme (CYP17) that carries out 2 reactions early in androgen synthesis - the 17a-hydroxylase step and the 17,20-lyase step (see earlier diagram)
- Initially used in adjuvant therapy with pituitary downregulators, now licensed for use in its own right
- Knock-on effects on synthesis/levels of other steroids, necessitating use of glucocorticoids to control blood pressure.
82
What does resistance to ADT cause?
How long does this take?
- Prostate tumour growth is initially androgen-dependent, and disease progress and treatment response are monitored by serum PSA levels.
- However, resistance to ADT can develop resulting in castration-resistant prostate cancer (CRPC) or metastatic castration-resistant prostate cancer (mCRPC).
- Median time to development of such hormone-independent relapse is biochemically (rise in blood PSA levels) after 1 year and symptomatically after 3 years.
- Patients with hormone-independent cancer treated with abiraterone also eventually progress, and therapies for this stage of disease are not very effective.
- Progression correlates with increase in PSA levels indicating reactivation of AR.
- Although the resistance is multifactorial, aberrations in AR are key drivers.
83
What are the best-characterised hormonal independence mechanisms for prostate cancer?
1. Loss of ligand specificity (mutation of the AR)
2. Active splice variants (AR-Vs)
3. AR overexpression
84
Describe the loss of ligand specificity: a hormonal independent mechanism for prostate cancer
- study image
- Mutations in the AR gene are rare in primary prostate tumours but occur in approximately 20% of CRPCs.
- Many significant AR mutations occur in the ligand binding domain, and can increase the sensitivity and/or decrease the specificity of ligand binding, allowing AR to be activated by other ligands.
85
Describe active splice variants (AR-Vs): a hormonal independent mechanism for prostate cancer
- study image
- AR-Vs are mutant forms that arise by gene rearrangement or aberrant splicing, and are observed both in prostate cancer cell lines and prostate tumours
- Many have been identified, with AR-V7 being most studied to date.
- All lack the ligand-binding domain (LBD), which removes the necessity for ligand activation, but since they contain AF1 and the DNA-binding domain (DBD) they are constitutively active, and regulate the majority of AR-dependent genes - including genes that promote cell/tumour growth.
86
Describe AR overexpression: a hormonal independent mechanism for prostate cancer
- 30-50% of CRPC tumours have increased levels of AR due to gene amplification or overexpression.
- This allows increased sensitivity to low levels of androgens, or weaker androgens, so amplifying the response.
87
Describe alteration in cofactor levels: a hormonal independent mechanism for prostate cancer
- As for breast cancer, increased levels of coactivators can promote increased sensitivity to hormones.
- Conversely, decreased levels of corepressors may prevent the action of antiandrogens (and, in breast cancer, antioestrogens).
- Corepressors have the opposite effect to coactivators, increasing chromatin condensation and restricting access of polymerase, hence inhibiting transcription
- Antiandrogens (and antioestrogens) are believed to alter the receptor in ways that can promote their interaction with corepressors, so corepressors may be required for the repressive function of antiandrogens in the treatment of prostate cancer.
- Corepressor loss is believed to promote failure of these therapies.
- In summary, variation in levels of cofactors could explain the hormone-resistance seen in many initially hormone-dependent tumours.
- Further, the ratio of coactivators to corepressors in target tissue may affect the outcome of hormonal treatment – determining whether partial agonists activate or inhibit receptor-dependent transcription.
88
Why is the PSA test performed to detect prostate cancer?
Discuss the pros and cons of this method
89
Why are breast and prostate cancer discussed together?
- they have very similar glandular architecture
- as can be seen in the image, the glands are exocrine glands, branching to
- ending at the urethra for the prostate
- ending at the nipple for breast
- although these glands are exocrine, we are looking at endocrine cancer, so we are looking at the internal hormones which act on these glands
90
Describe the challenges of the different types of hormone-dependent breast and prostate cancers
91
Describe the action of the key hormonal treatment for breast cancer: SERM (selective estrogen receptor modulator)
- Example
- Function
- Therapeutic use
- Adverse effects
- Examples:
- Tamoxifen
- Raloxifene
- Function:
* Induce conformational change in ER
* Antagonist in mammary tissue, agonist in others?
* Stimulates cholesterol metabolism
* Increases bone density
* Increases cell proliferation in endometrium
- Therapeutic Use:
* Targeted anti-cancer treatment (ER+ve)
* Reduces risk of breast cancer
* Hot flushes
* Bone pain
* Nausea and fatigue
* Risk of endometrial cancer
92
Describe the action of the key hormonal treatment for breast cancer: SERD (selective estrogen receptor degrader)
- Example
- Function
- Therapeutic use
- Adverse effects
- Examples:
- Fulvestrant
- Function:
* Inhibits ER dimerization
* Accelerates ER degradation and reduces ER expression
- Therapeutic Use:
• Treatment of advanced and metastatic ER-positive breast cancer
- Adverse Effects:
* Nausea
* Vomiting
* Loss of appetite
* Muscle pain
* Hot flushes
93
Describe the action of the key hormonal treatment for breast cancer: Aromatase inhibitors
- Example
- Function
- Therapeutic use
- Adverse effects
- Examples:
- Anastrazole, Exemestane, Letrozole
- Function:
* Inhibit aromatase to block conversion of testosterones to oestrogens
* Type I: irreversible inhibitor
* Type II: reversible inhibitor
- Therapeutic use:
• Treatment of breast cancer in postmenopausal women
- Adverse Effects:
* Hot flushes
* Joint and muscle pain
* Loss of bone mineral density
94
Describe the action of the key hormonal treatment for prostate cancer: Pituitary downregulators
- Example
- Function
- Therapeutic use
- Adverse effects
- Example:
- Goserelin, Leuprolelin, Cetrorelix
- Function:
* GnRH “super” analogue
* OR – GnRH antagonist
* Inhibit production of LH and testosterone through inhibition of the pituitary-gonadal axis
- Therapeutic use:
* Inoperable Prostate cancer, first-line treatment
* ± antiandrogen
* Breast cancer, endometriosis
* Ovulation suppression (IVF)
- Adverse effects:
* Hot flushes
* Sweating
* Headache and dizziness
* Impotence
* Osteoporosis
95
Describe the action of the key hormonal treatment for prostate cancer: Antiandrogens / SARMs
- Example
- Function
- Therapeutic use
- Adverse effects
- Examples:
- Enzalutamide, Bicalutamide, Cyproterone acetate
- Function:
* Bind to AR, affect different steps
* Partial or full antagonist
* Induce conformation change
* Do not reduce testosterone levels
- Therapeutic Use:
* prostate cancer, first line or once pituitary downregulation fails
* Alopecia/baldness
* Polycystic ovarian syndrome
- Adverse effects:
* Hot flushes
* Body aches and pains
* Headache and dizziness
* Impotence
* Breast growth
* Loss of muscle
* Osteoporosis
96
Describe the action of the key hormonal treatment for prostate cancer: Androgen synthesis inhibitors
- Example
- Function
- Therapeutic use
- Adverse effects
- Examples:
- Abiraterone
- Function:
* Inhibit CYP17 to reduce androgen production
* May affect both hydroxylase and lyase activity, or lyase alone
- Therapeutic use:
* Treatment of metastatic castration-resistant prostate cancer,
* May be adjuvant with pituitary downregulation
- Adverse effects:
* Joint swelling and pain
* Diarrhoea
* Hot flashes
* Vomiting
* High blood pressure
97
Learn this figure of the mechanism of action of different drugs on testosterone production and AR function
98
Observe this figure of how antiandrogens inhibit AR activity
99
Using this figure, describe the actions of key hormonal treatments for prostate cancer
- In the absence of glucocorticoid supplementation, abiraterone leads to compensatory elevation of serum adrenocorticotropic hormone levels and increased adrenal conversion of cholesterol to pregnenolone and progesterone (which does not require CYP17).
- The latter can function as an AR agonist by itself, and can also be converted to 3α5α-17-hydroxy-pregnanolone, and eventually to DHT via the backdoor pathway.
- Moreover, because mineralocorticoids are synthesized from progesterone (Figure 1), their production is spared when CYP17 is inhibited.
- As a result, accumulation of progesterone promotes mineralocorticoid excess and the development of the corresponding syndrome (fluid retention, edema, hypertension, and hypokalemia) that occurs in patients treated with abiraterone in the absence of corticosteroid replacement therapy.
- Therefore, the use of low-dose (replacement) corticosteroids is recommended in combination with abiraterone, to suppress the accumulation of pregnenolone, progesterone, and mineralocorticoids, in order to (1) decrease the risk of mineralocorticoid side effects and (2) enhance its anticancer activity.
100
Observe this figure of the mechanism of castrate-resistant prostate cancer
101
Are the mechanisms of resistance in anti-hormone treatments similar in both prostate and breast cancers?
- yes, look at the table which are categorised by their dependence on the hormone receptors or hormones themselves
102
Observe this figure of the key hormonal treatments for prostate cancer
