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
Where are the main corticosteroids and mineralocorticoids synthesised?
In the adrenal cortex
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 -> 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 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
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
What is the luminal structure of the mammary gland?
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
What is the etiology of breast cancer?
Age (normally >50) Genetic mutations (BRCA1 and 2) Reproductive history Previous radiotherapy to the chest or breasts Not physically active Overweight HRT for >5 yrs Pregnancy after 30, not breastfeeding and never having a full term pregnancy Drinking alcohol
What facets of the reproductive history increase the chance of breast cancer?
Early menstrual cycle onset (<12)
Menopause >55
What causes a ductal breast carcinoma in situ (DCIS)?
Cancer developing in ducts and staying there
Why do the cancer cells not spread more in DCIS?
Not yet developed the ability to spread
What is lobular breast carcinoma in situ?
Abnormal cells form in the milk glands
Is lobular breast carcinoma in situ cancer?
No but indicates there could be an increased risk of its development
What is the prognosis for estrogen and progesterone receptor positive cancers?
Good
What is the prognosis for estrogen and progesterone receptor negative cancers?
Poor
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 cauing 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?
Exemestane
Androgen analogue that binds nearby 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
What is the main function of normal prostate gland tissue?
Produce prostatic fluid that creates semen when mixed with the sperm produced by the testes
What type of gland is a prostate gland?
Exocrine
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?
Prostate inflammation due to infection
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
Where does prostate cancer start?
Luminal epithelium tissues
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 are the classes of prostate cancer?
T1-4,
N0-3,
M1a-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
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?
> 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 is the gleason grading system used for?
To help evaluate the prognosis of men using prostate biopsy samples
What are the stages in the gleason grading system?
1- small, uniform glands 2- more stroma between glands 3- distinctly infiltrative margins 4- irregular masses of neoplastic glands 5- only occasional gland formation
What are the treatments for prostate cancer?
Watchful waiting
Radical prostatectomy
Radical radiotherapy
Hormone therapy
What are the risk factors for prostate cancer?
Age Ethnicity Family history Inherited BRCA1/2 gene Men with lynch syndrome Diet Obesity Chemical exposures Inflammation of the prostate STIs
What is pten?
Phosphatase that antagonises the phosphatidylinositol 3-kinase signalling pathway
What does loss of pten result in?
Increased growth function signalling
How does TMP-RSS2 ERG fusion cause prostate cancers?
Androgen receptor drives proto-oncogene ERG which leads to inappropriate gene activation
What does abiratrone acetate do?
Inhibits testosterone synthesis in the adrenal gland
What are finasteride and dutasteride?
5 alpha reductase inhibitors
What are some examples of anti-androgen drugs?
Bicalutamide
Enzalutamide
Flutamide
Nilutamide
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
