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Dysfunction > IHDC > Flashcards

IHDC Flashcards

1
Q

What are the three groups of hormones?

A

→Steroids – lipid soluble small molecules e.g. testosterone

→Peptide / proteins e.g. insulin

→Modified amino acids / amine hormones e.g. adrenaline

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2
Q

What are steroid hormones synthesised from?

A

→cholesterol

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3
Q

Where are corticosteroids synthesised?

A

→adrenal cortex

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4
Q

Where are androgens and oestrogens synthesised?

A

→gonadal tissues

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5
Q

Which cancers are common for men and women?

A 
→women= breast
→men= prostate
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6
Q

What does the steroid-nuclear receptor complex bind to?

A

→to specific DNA sequences called response elements

→located in the promoters of steroid responsive genes

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7
Q

What are the key characteristics of nuclear receptors?

A

→Ligand binding domain (LBD)
→DNA binding domain (DBD)
→Activation function domain (AF1 & 2)- forms part of activation signal

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8
Q

What is the activation function domain of nuclear receptors?

A

→Recruits gene activation machinery,

→some receptors have a secondary AF2 domain towards the C-terminal

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9
Q

What does binding of steroids to steroid receptors cause?

A

→physical restructuring of the polypeptide chains in the receptor, activating it

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10
Q

what happens when ligands bind to the ligand binding site of receptors?

A

→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

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11
Q

What does the DNA binding domain contain?

A

→2 zinc fingers domains

→Interaction with the DNA phosphate backbone

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12
Q

What are hormone response elements?

A

→specific DNA sequences found in the promoters of hormone responsive genes

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13
Q

What is characteristic of hormone response elements?

A

→Many are palindromic

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14
Q

How many nuclear receptor genes in humans?

A

→48 nuclear receptor genes

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15
Q

What do steroid receptors share and differ in?

A

→high homology in the DNA binding domain

→differ in ligand binding domains, and differ in N-terminal activation domains

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16
Q

What type of gland is the breast?

A

→apocrinegland

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17
Q

What is the breast composed of?

A

→glands and ducts

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18
Q

What are lobes in the breast?

A

→milk-producing part of the breast

→15-20 sections

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19
Q

Where are lobules found?

A

→lobes

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20
Q

What is the difference between endocrine and exocrine glands?

A

→Exocrine glands – secrete substances out onto a surface or cavity, via a ductal structure.

→Endocrine glands – secrete substances directly into the bloodstream

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21
Q

What type of glands are apocrine glands?

A

→specialised exocrine gland in which a part of the cells’ cytoplasm breaks off releasing the contents

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22
Q

What are the two cell types in mammary epithelium?

A

→luminal

→basal

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23
Q

What are luminal cells in mammary epithelium?

A

→form a single layer of polarized epithelium around the ductal lumen, luminal cells produce milk during lactation

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24
Q

What are basal cells in mammary epithelium ?

A

→cells that do not touch the lumen
→in contact with the basement membrane
→also known as myeoepithelium

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25
Q

Which cells in mammary epithelium contracts during lactation?

A

→ basal

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26
Q

Which cells in mammary epithelium produces milk?

A

→luminal

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27
Q

What are the two phases of mammary gland development?

A

→hormone-independent from embryonic development up to puberty

→hormone-dependent during puberty, menstrual cycle and pregnancy

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28
Q

What does hormone dependent mammary development result in?

A

→ductal elongation

→triggers side branching

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29
Q

Which hormone switches on the progesterone receptor?

A

→oestrogen

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30
Q

What is the effect of progesterone on ducts?

A

→branching of the ducts

→together with prolactin hormone

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31
Q

What is the effect of prolactin on ducts?

A

→alveologenesis

→lactogenic differentiation

32
Q

Where does breast cancer begin?

A

→commonly in the cells that line the milk ducts of the breast

33
Q

What genes are implicated in breast cancers?

A

→BRCA1 and BRCA2

34
Q

Which ages are risk factors for breast cancers?

A

→menstrual cycle before 12yrs

→menopause after 55yrs

35
Q

What is ductal breast carcinoma in situ?

A

→When cancer cells develop within the ducts of the breast but remain within the ducts

36
Q

What is lobular breast carcinoma in situ?

A

→abnormal cells form in the milk glands lobules

→this is not cancer but could be increased risk

37
Q

What receptors do luminal cells have?

A

→oestrogen

38
Q

What is the prognosis for ER+ and ER- cancers?

A

→ER/PR+= good prognosis

→ER- = poor prognosis
→cannot be treated hormonally

39
Q

What happens in ER breast cancer to cause over transcribing of genes?

A

→ER’s ability to bind DNA and open chromatin becomes hijacked
→transcribe many genes, non-coding RNAs and miRNAs

40
Q

What percentage of breast cancers are ER+?

A

→75%

41
Q

Give examples of drugs to treat breast cancer

A

→tamoxifen
→aromatase inhibitors
→Fulvestrant

42
Q

What is fulvestrant?

A

→an analogue of estradiol

→competitively inhibits binding of estradiol to the ER

43
Q

How does fulvestrant work?

A

→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

44
Q

Why is any fulvestrant-ER complex inactive?

A

→both AF1 and AF2 are disabled

45
Q

What is the mechanism of tamoxifen?

A

→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

46
Q

What are the differential activation of tamoxifen?

A

→activates ER in the uterus and liver

→antagonist in breast tissue.

47
Q

Describe the mechanism of aromatase inhibitors type 1 of breast cancer treatment

A

→androgen analogues and bind irreversibly to aromatase

48
Q

Describe the mechanism of aromatase inhibitors type 2 of breast cancer treatment

A

→contain a functional group within the ring structure that binds the heme iron of the cytochromeP450,

→interferes with the hydroxylation reactions

49
Q

Describe the conversion of androgens to oestrogen

A

→Conversion of ketone group

→Aromatic ring is formed with an alcohol group

50
Q

What type of gland is the prostate?

A

→apocrine

51
Q

What can lead to hyperplasia and prostate cancer in old age?

A

→reactivation of prostate growth

52
Q

What is an example of dysregulated growth of prostate?

A

→Benign Prostatic Hyperplasia

53
Q

What are the symptoms of prostate cancer?

A 
→frequent trips to urinate
→poor urinary stream
• urgent need to urinate 
• hesitancy whilst urinating
• lower back pain 
• blood in the urine (rare)
54
Q

Where does prostate cancer start from?

A

→luminal cells

55
Q

What are the three ways to detect prostate cancer?

A

→Digital rectal examination (DRE)
→PSA test
→Ultrasound

56
Q

Why is ultrasound used in detecting prostate cancer?

A

→To detect tumour outside prostate capsule

57
Q

What are the 4 stages of prostate cancer?

A

→T1: Small, localised tumour
→T2 : Palpable tumour
→T3: Escape from Prostate Gland
→T4: local spread to pelvic region

58
Q

How is prostate cancer staged?

A

→TNM system
→tumour- size
→node- number of lymph nodes
→metastasis

59
Q

What are the lymph nodes stages of prostate cancer?

A

→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

60
Q

What are the metastasis stages of prostate cancer?

A

→M1- non-regional lymph nodes

→M2- bone
→M3- other sites

61
Q

What are the morphological changes in prostate cancer cells?

A

→Loss of glandular structure

→irregular structure

62
Q

What system is used for grading prostate cancer?

A

→Gleason grading systemis used to help evaluate theprognosisof men using prostate biopsy samples

63
Q

How many stages in prostate cancer?

A

→5

64
Q

What are prostate cancer treatment approaches?

A

→• “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

65
Q

What are the current therapies for prostate cancer?

A

→Watchful weighting- recommended for old age

→Active surveillance- PSA tests, MRI scans and biopsies

66
Q

What are the risk actors for prostate cancer?

A 
→age 
→race- more common in Afro-Carribean
→Geography- most common in western Europe, and America
→family history
→gene changes- Lynch syndrome
→obesity
→diet
67
Q

What are gene mutations associated with prostate cancer?

A

→BRCA1

→PTen

68
Q

What is PTen?

A

→a phosphatase that antagonizes the phosphatidylinositol 3-kinase signalling pathway

69
Q

What does loss of PTen result in?

A

→results in increased growth factor signalling.

70
Q

Which fusion is most frequent in prostate cancer?

A

→TMPRSS2 – ERG
→driven by testerone
→Androgen Receptor now influences ERG

71
Q

What is testosterone converted to as it crosses into the prostrate?

A

→Dihydrotestosterone (DHT)

72
Q

What are the treatments for prostate cancer?

A

→ suppressing the production of androgens
→specifically it inhibits CYP17A1
→reduces testoterone

73
Q

What are the two treatments addressing GnRH involvement in prostate cancer?

A

→Goserelin – super agonist

→Abarelix –antagonist

→reduces testoterone

74
Q

What drug is used to inhibit testosterone conversion to DHT?

A

→5a – reductase inhibitors

→Commonly used for
Benign Prostate Hyperplasia (BPH)

→Finasteride
Dutasteride (Avodart)

75
Q

What drugs are used as competitive anti-androgens/ androgen blockers?

A

→Bicalutamide
→Enzalutamide
→Flutamide
→Nilutamide

→compete for AR binding

76
Q

What structure folds over the active transcription factor and can be inhibited?

A

→AR Helix 12 folds over

77
Q

What are some events leading to ineffective hormone therapy?

A

→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

Dysfunction (29 decks)

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