Introduction To Hormone Dependant Cancers: Breast And Prostate Cancers Flashcards
What is a hormone?
Chemical messenger made by specialist cells and is released into the bloodstream to have an effect in another part of the body
Where are hormones produced?
- Pineal gland
- Hypothalamus
- Pituitary
- Thyroid
- Thymus
- Pancreas
- Adrenal cortex
What are the three groups of hormones?
- Steroids
- Peptide/proteins
- Modified amino acids/amine hormones
What are steroids synthesised from?
Cholesterol
Which tissue in the adrenal glands are steroid synthesised?
In the adrenal cortex
Name 5 different classes of steroids
- androgen (testosterone)
- estrogen (estradiol)
- progestogen (progesterone)
- corticosteroids (cortisol)
- mineralocorticoids (aldosterone)
Name the 2 most prevalent cancers in the UK
- breast
- prostate
Both tissues are heavily influenced by steroid hormones - these tissues are hormone dependant. So the cancer can also be dependant on hormones.
What are steroid response elements - describe their structure?
Specific sequences in the DNA on promoters where the steroid-receptor complex binds to. So the steroid + receptor complex acts as a TF.
- many are palindromic repeats
- hormone response elements for estrogen are called estrogen response elements etc.
Name the 3 domains in all steroid nuclear receptors
- LBD - ligand binding domain
- DBD - DNA binding domain
- AF1 and AF2 - activation function domain
What is the function of the AF1 domain?
Activation function domains -
Recruits gene activation machinery, some receptors have AF2 further towards the C terminal
Describe the general mechanism of steroid receptors
- This is after the ligand binds to LBD that changes its structure to activate it.
- Also, some of the receptors will dimerise.
- Hormone responsive genes can be downregulated or upregulted and many hundreds of genes can be regulated by a steroid receptor
What are sex hormones responsible for?
Sexual dimorphism between males and females and development of secondary sexual characteristics
What are the effects of female sex steroid hormones?
Oestrogen controls the menstrual cycle and breast tissue development, fertility and reproductive organ development
What are the effects of male sex steroid hormones?
Testosterone controls reproductive and supportive organs (prostate) and development of secondary characteristics
Why are breast/prostate cancer the most commonly diagnosed?
- Tissues are hormone dependant
- Steroids control several aspects of cellular proliferation, tissue function, gene expression and morphology
What is the steroid mechanism of action?
- Enters cell and binds to cytoplasmic receptor
→ Conformational change in the receptor (causing it to become activated) → dissociated from the cytoplasmic proteins and translocates into the nucleus
→ receptor binds to DNA promoter regions and act as transcription factors and induces gene expression
What are the key characteristics of a nuclear receptor?
- Ligand binding domain
- DNA binding domain
- Activation function domain
- Ligand activated
What does the ligand binding domain of a nuclear receptor do?
Binds specific steroids with a high affinity
What does the DNA binding domain of a nuclear receptor do?
Binds specific DNA sequences
What does the activation function domain of a nuclear receptor do?
Recruits gene activation machinery, some receptors have a secondary af2 domain towards the c-terminal
What does ligand binding to the ligand binding site cause?
A shift in the alpha helix, which activates the receptor
How are hormone responsive genes controlled?
Up or down regulated by steroid hormones
What are hormone response elements?
Specific DNA segments found in the promoters of hormone response genes
What are hormone response elements made up of?
6 bases, 3 spacer DNA bases, 6 bases
How many genes are contained in the nuclear receptor superfamily?
48
What do the nuclear receptor superfamily share?
Common domain receptor structure
What does the main steroid receptor depend on?
The thing they bind
What is a zinc finger domain?
Zinc finger, binds to hormone response elements:
- CI Zinc finger
- CII Zinc finger
Describe the function of CI Zinc finger?
specific DNA sequence binding
Describe the function of CII Zinc finger
interaction with the DNA phosphate backbone
What is the breast?
Breast is an apocrine gland that produces milk
What is the mammary gland tissue composed of?
Glands and ducts that produce fatty breast milk
What is the type of the gland that produces milk?
Apocrine gland
What is the milk producing part of the breast organised into (and what are they called)?
- 15-20 sections called lobes
- within each lobe is lobules, where milk is produced
What does milk travel through in the breast?
Networks of tiny tubules called ducts
What does an exocrine gland do?
Secretes substances out onto a surface or cavity via a ductal structure
What does an endocrine gland do?
Secrete substances directly into the bloodstream
What is an apocrine gland?
Specialised exocrine gland in which a part of the cell’s cytoplasm breaks off, releasing the contents
Describe the 2 cell types in the mammary gland
- Luminal
- Basal
What is the function of the luminal cells in the mammary gland?
Luminal cells form a single layer of polarised epithelium and the ductal lumen
What do luminal cells produce (And when?)
Milk during lactation
What is the basal mammary gland tissue structure?
Comprise the cells that do not touch the lumen and basally orient the epithelial cells in contact with the basement membrane
What are the two major phases in mammary gland development and when do they happen?
- Hormone independant (embryonic → puberty)
- Hormone dependant (after puberty)
What does hormone dependant mammary gland development cause?
Ductal elongation and side branching
In an adult what does estrogen allow for in the breast?
Maintenance of mammary gland tissue and primes it for the effects of progesterone during pregnancy for milk production
Describe the differing effects of oestrogen, progesterone and prolactin on the ducts in the mammary glands (think about their roles in the endometrium)
- Oestrogen causes ductal elongation (so mostly growth?)
- Progesterone causes ductal elongation and side branching (differentiation?)
- Prolactin causes alveogenesis and lactogenic differentiation
What is the aetiology of breast cancer (not including normal cancer ones)?
- genetic mutations such as BRCA1 and BRCA2
- reproductive history (early onset of menstrual cycle before 12 years and starting menopause after 55 years means that women are exposed to hormones for longer)
- previous radiotherapy to the chest
- taking hormones including certain oral contraceptives
- first pregnancy after 30,
What facets of the reproductive history increase the chance of breast cancer?
- Early menstrual cycle onset (before 12)
- Menopause after 55
What is meant by DCIS?
DCIS = ductal carcinoma in situ
What causes a ductal breast carcinoma in situ (DCIS)?
- This is when cancer cells develop in the ducts and remain in the ducts
Why do the cancer cells not spread more in DCIS?
Not yet developed the ability to spread
What is meant by LCIS?
Lobular carcinoma in situ - when the abnormal cells are in the milk glands (lobules)
Is lobular breast carcinoma in situ cancer?
No but indicates there could be an increased risk of its development
Which tissue of the breast does most cancer arise from and what receptor do they express?
Luminal cells, expressing ER (oestrogen receptor)
What is the prognosis for estrogen and progesterone receptor positive cancers?
Good
What is the prognosis for estrogen and progesterone receptor negative cancers?
Poor
Describe the role of the ER receptor in breast cancer
- ER’s ability to bind to DNA and open chromatin becomes hijacked and is used to transcribe many genes, non-coding RNAs and miRNAs
- ER then governs many genes involved in cell proliferation, metastasis, invasion and adhesion
- Breast cancer cells retain the mammary gland dependency on oestrogen so we can block ER receptor in treatment
Describe in detail how oestrogen exerts its effects in a cell
- Goes across membrane, binds to LBD, receptor dimerises
- receptor dimer binds to DNA at specific sites, AF1 and AF2 activated
- → so many coactivators are recruited to regulate gene expression of certain genes
How are estrogen and progesterone receptor negative cancers treated?
Hormonally
What happens when the estrogen receptor pathway is subverted?
ER’s ability to bind DNA and open chromatin is hijacked and used to transcribe many genes and RNAs
It then governs cancer cell proliferation
What is fulvestrant?
Analogue of estradiol
How does fulvestrant work?
Competitively inhibits binding of estradiol to the ER, with a binding affinity that is 89% that of estradiol
What does the fulvestrant- ER complex do?
Impairs receptor dimerisation and energy dependant nucleo-cytoplasmic shuttling. This blocks nuclear localisation of the receptor
How does tamoxifen work?
Binds to the ER at the ligand binding site
Is tamoxifen an agonist or an antagonist?
Agonist in uterus but antagonist in breast tissue
What happens to tamoxifen bound ER?
Doesnt fold properly and AF2 domains do not function,
Where does estradiol normally bind to the ER?
Deep within a pocket in the receptor
What happens when estradiol binds to ER?
Covered by a loop of protein chain, which is its active configuration
How does tamoxifen affect the binding of estradiol to the ER?
Binds to the chain that covers bound estradiol causing it to be too bulky to cover it, so it cant adopt its active conformation
Where does estrogen come from in post-menopausal women?
Peripheral conversion of androgens by blood vessels
Where is the aromatase enzyme present?
Adipose tissue, brain, blood vessels, skin, bone, endometrium and breast tissue
What is a type 1 aromatase inhibitor?
androgen analogues and bind irreversibly to aromatase
What is an example of a type 1 aromatase inhibitor?
Exemestone
What is the duration of type 1 aromatase inhibitor effect dependant on?
Rate of de novo aromatase synthesis
What is an example of a type 2 aromatase inhibitor?
Mastozole
What do type 2 aromatase inhibitors contain?
Functional group within the ring structure that binds to the haem iron of cytochrome P450, interfering with hydroxylation reactions
What is the main function of normal prostate gland tissue?
Produces prostatic fluid to add to the semen when mixed with other secretions and sperm
What type of gland is a prostate gland?
Exocrine (apocrine)
What are the 3 main types of cells found in the prostate?
- luminal epithelial cells
- basal epithelial cells
- stromal smooth muscle cells
What are the steps in prostate development?
- Hormone independant (embryo → puberty)
- Englargement during puberty
- Hormone dependant maintenance in adulthood
- Reactivation of prostate growth in old age
What is prostatitis?
- abnormalities of the prostate
- Prostate inflammation due to infection - can cause infertility
Describe what BPH is
- Abnormality of the prostate
- BPH is benign prostatic hyperplasia which is the benign dysregulated growth of the prostate
What are the two types of dysregulated prostate growth?
- Benign - benign prostatic hyperplasia
- Malignant - prostate cancer
What are the symptoms of prostate cancer?
- Frequent urination
- Poor urinary stream
- Urgent need to urinate
- Hesitancy while urinating
- Lower back pain
- Blood in urine
Which cell type does prostate cancer usually start in?
In the luminal epithelium (like in breast cancer)
What is meant by prostatic intarepithelial neoplasia vs invasive adenocarcinoma?
Prostatic intraepithelial neoplasia is what happens first before becoming an invasive adenocarcinoma when there is cancer of the luminal epithelium of the prostate
What does hyperproliferation of the luminal epithelium cause?
Prostate intraepithelial neoplasia
How can prostate cancer be detected?
- Digital rectal examination
- PSA test (prostate antigen blood test)
- Ultrasound
What is meant by the TNM staging of cancer?
- T is the size
- N is if spread to the lymph nodes involved
- M is if it has metastasised
What are the classes of prostate cancer?
- T (1-4)
- N (0-3)
- M (1a-c)
What is a T1 tumour?
Small localised tumour
What is a T2 tumour?
Palpable tumour
What is a T3 tumour?
Escape from prostate gland
What is a T4 tumour?
Local spread to pelvic region
Explain the grading of a biopsy staining by Gleason’s grading system
- Grades the sample based on how poorly differentiated the tissue is as a cancerous tissue will be very undifferentiated in comparison to the healthy tissue as seen in the image above.
- Higher Gleason score means the cancer is more aggressive and has a worse prognosis.
What is a N0 tumour?
No cancer in any lymph nodes
What is a N1 tumour?
One positive lymph node <2cm big
What is a N2 tumour?
more than 1 positive lymph node or one 2-5 cm big
What is a N3 tumour?
Any positive lymph node >5cm across
What is a M1a tumour?
Non-regional lymph nodes
What is a M1b tumour?
Bone
What is a M1c tumour?
Other sites
What are the stages in the gleason grading system?
- small, uniform glands
- more stroma between glands
- distinctly infiltrative margins
- irregular masses of neoplastic glands
- only occasional gland formation
Name some treatment options for different prostate cancer stages
- ‘Watchful waiting’ for low grade tumour in older patients
- Radical Prostatectomy for stage T1 or T2 (confined to prostate)
- Radical Radiotherapy for up to T3
- Hormone therapy often done alongside surgery or radiotherapy
Explain a large difficult with prostate cancers
Prostate cancer is highly variable in the sense that in some men it is harmless but in others it can be extremely deadly and it is unknown what makes a cancer very aggressive as opposed to being slow growing
Name some risk factors of prostate cancer
- Genetic risk genes (BRCA1 and BRCA2, HNPCC)
- Age (rare in men younger than 40, rises rapidly after 50)
- Race or ethnicity (less in asian people and more in black people - could be cultural as well as genetic)
- Diet, obesity, chemical exposures, inflammation of the prostate, STDs
Name the main gene mutations found in prostate cancer
- BRCA1 and PTen loss
- TMPRSS2-ERG
- Various other miRNA changes and point mutations
Describe what PTen is
A phosphatase that antagonises the PIP3 kinase pathway - it is the only known 3’ phosphatase counteracting this pathway
What does loss of pten result in?
Loss of PTEN causes increased growth factor signalling so causes cell survival and decreased apoptosis
Explain what TMPRSS2-ERG is
Is the most frequent fusion gene found in prostate cancers (40-80% of all prostate cancers in humans)
- AR (androgen receptor) will drive the TMPRSS2 gene which has a hormone sensitive promoter
- When this promoter fuses to ERG (a proto-oncogene) then ERG is upregulated in response to testosterone and becomes an oncogene
Describe the role of testosterone with the prostate and prostate cancer
Growth and development of the prostate is dependant on androgens including the most common, testosterone - it is androgen dependant for survival
- androgens are a key driver for prostate cancer growth so we can block AR in treatment
Where is the testosterone receptor present in the prostate?
Luminal epithelial cells (not basal or stromal)
What happens to testosterone when it enters the cell, does it just bind to AR?
No, it is first converted into DHT (dihydrotestosterone) by 5-alpha reductase before binding to AR and then dimerising and then binding to ARE (androgen response elements) on DNA
Where are androgenic precursors synthesised?
Adrenal glands secreted into blood, then converted in the testes to testosterone. The main two are:
- androsteinone
- dehydroepiandrosterone
Describe how Abiraterone acetate (ZYTIGA) functions
Inhibits the synthesis of adrenal androgens (precursors to testosterone) so that testosterone can not be synthesised in the testes
Name other ways to stop testosterone signalling in the prostate
- Inhibition of the HPA axis such as synthetic peptides
- 5 alpha reductase inhibition
- AR binding competition
What are some examples of synthetic peptides?
- Goserelin = super agonist to GnRH
- Abarelix = antagonist to GnRH
What are finasteride and dutasteride?
5 alpha reductase inhibitors
Describe how Finasteride works
Is a 5 alpha reductase inhibitor so less testosterone can become DHT
What are some examples of anti-androgens?
- Bicalutamide
- Enzalutamide
- Flutamide
- Nilutamide
Describe how Bicalutamide works
Competitive antagonist for AR so competes with testosterone for the LBD
What are 5 alpha reductase inhibitors commonly used for?
Benign prostate hyperplasia
What happens to hormone therapies over time?
Become less and less effective because cells develop mechanisms to overcome hormonal starvation
What kind of mechanisms can tumours develop to overcome hormonal starvation?
- Tumours start to synthesise their own steroid hormones
- Mutations making ligand binding sites less specific
- Receptor bypass
- Receptor cofactor amplification
- Antagonists become agonists via ligand binding domain mutations
What is the ARV7?
- Androgen receptor variant 7
- Is a variant that is truncated without the C terminus and is active without the ligand in some prostate cancers
Explain what receptor cofactor amplification is
- Another mechanism for prostate cancer hormone therapy resistance
- Is the amplification of cofactors causing the cell to be more sensitive to low levels of the hormone (signal is amplified more)
Describe one more mechanism for resistance to hormonal therapies, but this one is specific to prostate cancers
- A mutation in the LBD of the AR (androgen receptor) that causes antagonists to the receptor to become agonists and activate the receptor
- These therapies would actually drive the disease in this case
