IHDC Flashcards
What are the three groups of hormones?
→Steroids – lipid soluble small molecules e.g. testosterone
→Peptide / proteins e.g. insulin
→Modified amino acids / amine hormones e.g. adrenaline
What are steroid hormones synthesised from?
→cholesterol
Where are corticosteroids synthesised?
→adrenal cortex
Where are androgens and oestrogens synthesised?
→gonadal tissues
Which cancers are common for men and women?
→women= breast →men= prostate
What does the steroid-nuclear receptor complex bind to?
→to specific DNA sequences called response elements
→located in the promoters of steroid responsive genes
What are the key characteristics of nuclear receptors?
→Ligand binding domain (LBD)
→DNA binding domain (DBD)
→Activation function domain (AF1 & 2)- forms part of activation signal
What is the activation function domain of nuclear receptors?
→Recruits gene activation machinery,
→some receptors have a secondary AF2 domain towards the C-terminal
What does binding of steroids to steroid receptors cause?
→physical restructuring of the polypeptide chains in the receptor, activating it
what happens when ligands bind to the ligand binding site of receptors?
→shift in an a-helix, activating the receptor
→Receptor dimerises
→moves into the nucleus and binds to specific DNA sequences
→recruits DNA modifying enzymes e.g. histone deacetylases, other transcription factors and RNA polymerase to promoters of hormone responsive genes
What does the DNA binding domain contain?
→2 zinc fingers domains
→Interaction with the DNA phosphate backbone
What are hormone response elements?
→specific DNA sequences found in the promoters of hormone responsive genes
What is characteristic of hormone response elements?
→Many are palindromic
How many nuclear receptor genes in humans?
→48 nuclear receptor genes
What do steroid receptors share and differ in?
→high homology in the DNA binding domain
→differ in ligand binding domains, and differ in N-terminal activation domains
What type of gland is the breast?
→apocrinegland
What is the breast composed of?
→glands and ducts
What are lobes in the breast?
→milk-producing part of the breast
→15-20 sections
Where are lobules found?
→lobes
What is the difference between endocrine and exocrine glands?
→Exocrine glands – secrete substances out onto a surface or cavity, via a ductal structure.
→Endocrine glands – secrete substances directly into the bloodstream
What type of glands are apocrine glands?
→specialised exocrine gland in which a part of the cells’ cytoplasm breaks off releasing the contents
What are the two cell types in mammary epithelium?
→luminal
→basal
What are luminal cells in mammary epithelium?
→form a single layer of polarized epithelium around the ductal lumen, luminal cells produce milk during lactation
What are basal cells in mammary epithelium ?
→cells that do not touch the lumen
→in contact with the basement membrane
→also known as myeoepithelium
Which cells in mammary epithelium contracts during lactation?
→ basal
Which cells in mammary epithelium produces milk?
→luminal
What are the two phases of mammary gland development?
→hormone-independent from embryonic development up to puberty
→hormone-dependent during puberty, menstrual cycle and pregnancy
What does hormone dependent mammary development result in?
→ductal elongation
→triggers side branching
Which hormone switches on the progesterone receptor?
→oestrogen
What is the effect of progesterone on ducts?
→branching of the ducts
→together with prolactin hormone
What is the effect of prolactin on ducts?
→alveologenesis
→lactogenic differentiation
Where does breast cancer begin?
→commonly in the cells that line the milk ducts of the breast
What genes are implicated in breast cancers?
→BRCA1 and BRCA2
Which ages are risk factors for breast cancers?
→menstrual cycle before 12yrs
→menopause after 55yrs
What is ductal breast carcinoma in situ?
→When cancer cells develop within the ducts of the breast but remain within the ducts
What is lobular breast carcinoma in situ?
→abnormal cells form in the milk glands lobules
→this is not cancer but could be increased risk
What receptors do luminal cells have?
→oestrogen
What is the prognosis for ER+ and ER- cancers?
→ER/PR+= good prognosis
→ER- = poor prognosis
→cannot be treated hormonally
What happens in ER breast cancer to cause over transcribing of genes?
→ER’s ability to bind DNA and open chromatin becomes hijacked
→transcribe many genes, non-coding RNAs and miRNAs
What percentage of breast cancers are ER+?
→75%
Give examples of drugs to treat breast cancer
→tamoxifen
→aromatase inhibitors
→Fulvestrant
What is fulvestrant?
→an analogue of estradiol
→competitively inhibits binding of estradiol to the ER
How does fulvestrant work?
→binding impairs receptor dimerisation and energy-dependent nucleo-cytoplasmic shuttling
→blocks nuclear localisation of the receptor
→fulvestrant – ER complex that enters the nucleus is transcriptionally inactive
→accelerated degradation of the ER protein
Why is any fulvestrant-ER complex inactive?
→both AF1 and AF2 are disabled
What is the mechanism of tamoxifen?
→a partial agonist but does not cause the full activation of ER
→binds to the receptor making the extra tail of the drug too bulky
→ receptor loop is not able to form active conformation
What are the differential activation of tamoxifen?
→activates ER in the uterus and liver
→antagonist in breast tissue.
Describe the mechanism of aromatase inhibitors type 1 of breast cancer treatment
→androgen analogues and bind irreversibly to aromatase
Describe the mechanism of aromatase inhibitors type 2 of breast cancer treatment
→contain a functional group within the ring structure that binds the heme iron of the cytochromeP450,
→interferes with the hydroxylation reactions
Describe the conversion of androgens to oestrogen
→Conversion of ketone group
→Aromatic ring is formed with an alcohol group
What type of gland is the prostate?
→apocrine
What can lead to hyperplasia and prostate cancer in old age?
→reactivation of prostate growth
What is an example of dysregulated growth of prostate?
→Benign Prostatic Hyperplasia
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 (rare)
Where does prostate cancer start from?
→luminal cells
What are the three ways to detect prostate cancer?
→Digital rectal examination (DRE)
→PSA test
→Ultrasound
Why is ultrasound used in detecting prostate cancer?
→To detect tumour outside prostate capsule
What are the 4 stages of prostate cancer?
→T1: Small, localised tumour
→T2 : Palpable tumour
→T3: Escape from Prostate Gland
→T4: local spread to pelvic region
How is prostate cancer staged?
→TNM system
→tumour- size
→node- number of lymph nodes
→metastasis
What are the lymph nodes stages of prostate cancer?
→N0-No cancer cells found in any lymph nodes
→N1- 1 positive lymph node < 2cm across
→N2- >1 positive lymph node or 1 between 2-5cm across
→N3- Any positive lymph node > 5 cm across
What are the metastasis stages of prostate cancer?
→M1- non-regional lymph nodes
→M2- bone
→M3- other sites
What are the morphological changes in prostate cancer cells?
→Loss of glandular structure
→irregular structure
What system is used for grading prostate cancer?
→Gleason grading systemis used to help evaluate theprognosisof men using prostate biopsy samples
How many stages in prostate cancer?
→5
What are prostate cancer treatment approaches?
→• “Watchful waiting- Low grade tumour, older patients
→Radical prostatectomy- Stage T1 or T2 (confined to prostate gland)
→Radical radiotherapy-External up to T3 (spread past capsule) Internal implants (brachytherapy) for T1/2
→Hormone therapy- ± prostatectomy or radical radiotherapy, metastatic
What are the current therapies for prostate cancer?
→Watchful weighting- recommended for old age
→Active surveillance- PSA tests, MRI scans and biopsies
What are the risk actors for prostate cancer?
→age →race- more common in Afro-Carribean →Geography- most common in western Europe, and America →family history →gene changes- Lynch syndrome →obesity →diet
What are gene mutations associated with prostate cancer?
→BRCA1
→PTen
What is PTen?
→a phosphatase that antagonizes the phosphatidylinositol 3-kinase signalling pathway
What does loss of PTen result in?
→results in increased growth factor signalling.
Which fusion is most frequent in prostate cancer?
→TMPRSS2 – ERG
→driven by testerone
→Androgen Receptor now influences ERG
What is testosterone converted to as it crosses into the prostrate?
→Dihydrotestosterone (DHT)
What are the treatments for prostate cancer?
→ suppressing the production of androgens
→specifically it inhibits CYP17A1
→reduces testoterone
What are the two treatments addressing GnRH involvement in prostate cancer?
→Goserelin – super agonist
→Abarelix –antagonist
→reduces testoterone
What drug is used to inhibit testosterone conversion to DHT?
→5a – reductase inhibitors
→Commonly used for
Benign Prostate Hyperplasia (BPH)
→Finasteride
Dutasteride (Avodart)
What drugs are used as competitive anti-androgens/ androgen blockers?
→Bicalutamide
→Enzalutamide
→Flutamide
→Nilutamide
→compete for AR binding
What structure folds over the active transcription factor and can be inhibited?
→AR Helix 12 folds over
What are some events leading to ineffective hormone therapy?
→tumour start to synthesise their own steroid hormones
→Ligand binding site mutations make the receptors promiscuous
→Signal amplification, and increased sensitivity to low hormone levels
→Cross over with other signal pathways e.g. growth factors can phosphorylate and activate receptors
→generation of receptor variants eg without terminus
→cofactor amplification
→antagonist for prostate treatment become potent activator
