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omgmbd > L27: Intro To Hormone Dependent Cancers: Breast & Prostate Cancer > Flashcards

L27: Intro To Hormone Dependent Cancers: Breast & Prostate Cancer 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
Which cells in mammary epithelium contracts during lactation?
→ basal
26
Which cells in mammary epithelium produces milk?
→luminal
27
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
28
What does hormone dependent mammary development result in?
→ductal elongation | →triggers side branching
29
Which hormone switches on the progesterone receptor?
→oestrogen
30
What is the effect of progesterone on ducts?
→branching of the ducts | →together with prolactin hormone
31
What is the effect of prolactin on ducts?
→alveologenesis | →lactogenic differentiation
32
Where does breast cancer begin?
→commonly in the cells that line the milk ducts of the breast
33
What genes are implicated in breast cancers?
→BRCA1 and BRCA2
34
Which ages are risk factors for breast cancers?
→menstrual cycle before 12yrs | →menopause after 55yrs
35
What is ductal breast carcinoma in situ?
→When cancer cells develop within the ducts of the breast but remain within the ducts
36
What is lobular breast carcinoma in situ?
→abnormal cells form in the milk glands lobules →this is not cancer but could be increased risk
37
What receptors do luminal cells have?
→oestrogen
38
What is the prognosis for ER+ and ER- cancers?
→ER/PR+= good prognosis →ER- = poor prognosis →cannot be treated hormonally
39
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
40
What percentage of breast cancers are ER+?
→75%
41
Give examples of drugs to treat breast cancer
→tamoxifen →aromatase inhibitors →Fulvestrant
42
What is fulvestrant?
→an analogue of estradiol | →competitively inhibits binding of estradiol to the ER
43
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
44
Why is any fulvestrant-ER complex inactive?
→both AF1 and AF2 are disabled
45
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
46
What are the differential activation of tamoxifen?
→activates ER in the uterus and liver | →antagonist in breast tissue.
47
Describe the mechanism of aromatase inhibitors type 1 of breast cancer treatment
→androgen analogues and bind irreversibly to aromatase
48
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 cytochrome P450,  →interferes with the hydroxylation reactions
49
Describe the conversion of androgens to oestrogen
→Conversion of ketone group | →Aromatic ring is formed with an alcohol group
50
What type of gland is the prostate?
→apocrine
51
What can lead to hyperplasia and prostate cancer in old age?
→reactivation of prostate growth
52
What is an example of dysregulated growth of prostate?
→Benign Prostatic Hyperplasia
53
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) ```
54
Where does prostate cancer start from?
→luminal cells
55
What are the three ways to detect prostate cancer?
→Digital rectal examination (DRE) →PSA test →Ultrasound
56
Why is ultrasound used in detecting prostate cancer?
→To detect tumour outside prostate capsule
57
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
58
How is prostate cancer staged?
→TNM system →tumour- size →node- number of lymph nodes →metastasis
59
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
60
What are the metastasis stages of prostate cancer?
→M1- non-regional lymph nodes →M2- bone →M3- other sites
61
What are the morphological changes in prostate cancer cells?
→Loss of glandular structure | →irregular structure
62
What system is used for grading prostate cancer?
→Gleason grading system is used to help evaluate the prognosis of men using prostate biopsy samples
63
How many stages in prostate cancer?
→5
64
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
65
What are the current therapies for prostate cancer?
→Watchful weighting- recommended for old age →Active surveillance- PSA tests, MRI scans and biopsies
66
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 ```
67
What are gene mutations associated with prostate cancer?
→BRCA1 | →PTen
68
What is PTen?
→a phosphatase that antagonizes the phosphatidylinositol 3-kinase signalling pathway
69
What does loss of PTen result in?
→results in increased growth factor signalling.
70
Which fusion is most frequent in prostate cancer?
→TMPRSS2 – ERG →driven by testerone →Androgen Receptor now influences ERG
71
What is testosterone converted to as it crosses into the prostrate?
→Dihydrotestosterone (DHT)
72
What are the treatments for prostate cancer?
→ suppressing the production of androgens →specifically it inhibits CYP17A1 →reduces testoterone
73
What are the two treatments addressing GnRH involvement in prostate cancer?
→Goserelin – super agonist →Abarelix –antagonist →reduces testoterone
74
What drug is used to inhibit testosterone conversion to DHT?
→5a – reductase inhibitors →Commonly used for Benign Prostate Hyperplasia (BPH) →Finasteride Dutasteride (Avodart)
75
What drugs are used as competitive anti-androgens/ androgen blockers?
→Bicalutamide →Enzalutamide →Flutamide →Nilutamide →compete for AR binding
76
What structure folds over the active transcription factor and can be inhibited?
→AR Helix 12 folds over
77
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

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