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Cancer Biology > CBIO5: Hormones and cancer > Flashcards

CBIO5: Hormones and cancer Flashcards

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1
Q

Define hormone

A

Hormones are naturally occurring substances produced in specific parts of our bodies and act as chemical messengers. They travel through the blood to control functions of other tissues and organs

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2
Q 
What hormones are released from these glands?
Pineal
Hypothalamus
Pituitary 
Thyroid
Parathyroid
Thymus
Adrenal cortex
Kidney
Pancreas
Testes
Ovary
Uterus
A 
Pineal: melatonin
Hypothalamus: dopamine
Pituitary: vasopressin
Thyroid: calcitonin
Parathyroid: PTH
Thymus: thymopoietin
Adrenal cortex: adrenaline
Kidney: erythropoietin
Pancreas: insulin
Testes: androgen
Ovary: oestrogen
Uterus: prolactin
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3
Q

What are the three classes of hormones?

A

peptide/protein hormones (e.g. insulin), amine hormones (e.g. adrenaline) and steroid hormones

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4
Q

Where are all steroid hormones derived from?

A

Cholesterol

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5
Q

What are the different steroid hormone classes?

A

Androgens, oestrogens, progestins, glucocorticoids and mineralocorticoids

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6
Q

How do steroid hormones bring about their action on cells?

A

Act directly on intracellular receptors due to their lipophilicity: steroid hormones enter cells through the lipid-rich plasma membrane and then bind to so-called nuclear receptors. Nuclear receptors are transcription factors that regulate gene expression and hence protein production.

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7
Q

How many nuclear receptors are there in humans?

A

48

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8
Q

The subset of nuclear receptors that mediate steroid hormone signalling are called what?

A

Steroid receptors

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9
Q

Breast and prostate cancers are examples of what type of cancers?

A

Hormone-dependent / Endocrine cancers

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10
Q

What pharmaceuticals can increase the risk of breast/ovarian cancer?

A
  • combined menopausal hormone therapy

- oestrogen-only therapy slightly increases the risk of endometrial cancer

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11
Q

What is Diethylstilbestrol (DES)?

A

A synthetic oestrogen that was given to some pregnant women during in the 1940s-70s to prevent miscarriages

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12
Q

What do 1) early onset puberty, 2) late menopause, 3) late or no first pregnancy have in common?

A

Increased breast cancer risk as they are all factors that increase exposure to oestrogen cycles

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13
Q

What does insulin increase the risk of?

A

Pancreatic, liver, kidney, stomach and respiratory cancers

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14
Q

What does insulin-like growth factors (IGFs) increase the risk of?

A

Prostate, breast and bowel cancers

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15
Q

What are the key differences between oestrogens and androgens?

A

Oestrogens (e.g. oestradiol/estradiol) are produced in ovaries and are required for development of female secondary sex characteristics. Androgens (e.g. testosterone) are mainly produced by the testes and are responsible for the development of male secondary sex characteristics. However, note that males and females each have both androgens and oestrogens – it is the ratio that is different.

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16
Q

What is the production of oestrogen and androgen regulated by? what is this hormone regulated by?

A

uteinizing hormone (LH) produced by the anterior pituitary gland. LH secretion is in turn regulated by gonadotropin-releasing hormone (GnRH)

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17
Q

what does de novo mean?

A

where cholesterol in synthesised in the liver: the synthesis process begins with cholesterol being taken into the steroid-producing cells

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18
Q

What are oestrogens and androgens responsible for?

A

Female and male secondary sex characteristics

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19
Q

What does LH induce the production of in Leydig cells in the testes and granulosa cells in the ovaries?

A

pregnenolone

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20
Q

What is pregnenolone converted into?

A

dehydroepiandrosterone (DHEA)

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21
Q

What is dehydroepiandrosterone (DHEA) converted into? (men)

A

two intermediates: androstenediol and androstenedione

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22
Q

In men, testosterone circulates in the blood bound to what?

A

serum sex hormone binding globulin (SHBG) and albumin

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23
Q

Free-form testosterone enters prostate cells where it is converted into what by what enzyme?

A

dihydrotestosterone (DHT) via 5alpha-reductase

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24
Q

Where other than the testis and ovaries is androgen produced?

A

Adrenal glands

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25
Q

What is dehydroepiandrosterone (DHEA) converted into? (women)
How does this occur?

A

Into oestrogens: oestrone, 17beta-oestradiol (E2) and oestriol. Androstenedione is aromatized and oxidised in this process

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26
Q

What is the main circulating oestrogen during reproductive years?

A

E2

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27
Q

What is the main circulating oestrogen during pregnancy?

A

Oestriol

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28
Q

What is the main circulating oestrogen during menopause?

A

Oestrone

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29
Q

From where can E2 be directly syntheised?

A

Testosterone

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30
Q

What is the feedback loop for testosterone and oestrogen?

A

Testosterone and the oestrogens negatively feedback onto pituitary LH and hypothalamic GnRH levels

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31
Q

Where is GnRH produced?

A

Hypothalamus

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32
Q

Where is the receptor for GnRH?

A

In the anterior pituitary

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33
Q

What does GnRH stimulate the release of?

A

LH/FSH

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34
Q

What does LH/FSH do?

A

Stimulates testosterone production from the interstitial cells of the testis; FSH stimulates oestrogen production from the ovary (FSH and LH have additional roles in the testis and ovary also)

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35
Q

What is a homodimer

A

A pair of the same molecule

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36
Q

What are response elements?

A

Oestrogen receptors (ERs) and androgen receptors (AR) bind as homodimers to specific DNA sites, known as response elements

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37
Q

Describe the structure of response elements for oestrogen and androgen

A

These consist of two 6-nucleotide sequences (which can vary slightly in sequence) separated by 3 unconserved nucleotides

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38
Q

What is the base sequence for Oestrogen and Androgen response elements?

A

EREs: 5’-(A/G)GGTCAnnnTGACC(T/C)-3’

AREs: 5’-GG(A/T)ACAnnnTGTTCT-3’
The 3 unconserved nucleotides are represented as n

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39
Q

What are the oestrogen receptors called?

A

ERα and ERβ, encoded by two distinct genes, ESR1 and ESR2, respectively

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40
Q

What are the three functional domains or ARs and ERs?

A
  1. N-terminal transcriptional regulation domain (with AF-1)
  2. DNA-binding domain (DBD)
  3. Ligand-binding domain (LBD with AF-2)
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41
Q

In the absence of a ligand, what is the AR doing?

A

Cytoplasmic and bound to receptor-associated proteins

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42
Q

When a ligand binds to AR, explain what happens

A

A conformational change in the LBD and the displacement of the receptor-associated proteins. This exposes the nuclear localisation signal (NLS) and promotes the binding of importins and microtubule-associated motor proteins which facilitates the translocation of the ligand-receptor complex into the nucleus.

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43
Q

How does ER compare to AR with regards to cytoplasmic/nuclear property?

A

ER is partially nuclear even in the absence of ligand

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44
Q

What is required for receptor dimerisation and ERE & ARE binding?

A

Ligand binding to ER/AR

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45
Q

What regulates the ability of the ligands (oestrogen/testosterone) to transactivate the target gene?

A

coregulators such as: coactivators and corepressors

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46
Q

Explain the mechanism for how ER-alpha causes transcription (ERE dependent)

A

In the nucleus, ER-alpha interacts with EREs and recruits coactivators such as steroid receptor coactivators e.g. SRC-1 in the p160 family, which then recruit CREB binding protein in the p300 family which has intrinsic histone acetyltransferase (HAT) activity. This histone acetylation near the ERE opens up the chromatin and facilitates RNA polymerase II transcription. RNA polymerase II is then phosphorylated by coactivators to form an elongation-competent form

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47
Q

How does ERE-independent signalling occur?

A

Wherein ER does not bind to the DNA itself, but interacts with transcription factors such as SP1 and AP1

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48
Q

What type of glands are the breast and prostate? What does this mean?

A

Exocrine: they secrete substances outside of the body via ducts

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49
Q

Where do 90% of breast and prostate cancers occur?

A

Luminal epithelial layer

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50
Q

How are 90% of breast and prostate cancers diagnosed?

A

Loss in the basal cell layer

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51
Q

Briefly describe the structure of the breast and the prostate glands

A

The breast and the prostate both consist of several branching glands and secrete fluids out of the body via the nipple or urethra

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52
Q

Can you list the three structural domains of oestrogen receptor and androgen receptor?

A

N-terminal, DNA-binding domain (DBD), Ligand-binding domain (LBD)

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53
Q

What is the difference between and exocrine gland and an endocrine gland?

A

An exocrine gland secretes substances to the outside of the body via one or more ducts, whereas an endocrine gland secretes substances that are retained in the body – normally these substances (for example hormones) are secreted directly into the blood.

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54
Q

There is evidence that when they are present in the same cells the action of ERβ can actually _____ that of ERα

A

oppose

55
Q

What is oestrogen responsible for in women?

A

growth and development of the uterus, fallopian tubes, vagina and breasts, shaping body contours and the pubertal growth spurt in long bones and epiphyseal closure

56
Q

What is oestrogen responsible for in men?

A

growth spurt, skeletal maturation and epiphyseal closure

57
Q

Explain the 5 steps of the menstrual cycle

A
  • GnRH is released from the hypothalamus
  • LH and FSH secretion from anterior pituitary stimulated
  • FSH and LH stimulates growth and maturation of ovarian follicles and FSH stimulates oestrogen release
  • LH induces ovulation and transforms the granulosa into the corpus luteum which is an actively secreting gland
  • Ovaries produce oestrogen and progesterone which negatively feedback onto hypothalamus and pituitary.
58
Q

Which organs express buth ERbeta and ERalpha?

A

Bones, breasts, cardiovascular system, testes/ovary

59
Q

1 in how many women will be diagnosed with breast cancer at some time in their life?

A

1 in 8

60
Q

What % of cancers diagnosed in women are breast?

A

31%

61
Q

What are the four stages involved in breast cancer?

A

1) ductal or lobular hyperproliferation
2) evolution into carcinoma in situ
3) invasive carcinoma
4) metastatic disease

62
Q

What are the risk factors for breast cancer?

A

1) Age (4/5 above 50)
2) Family history (first-degree female relative doubles risk)
3) Genetics (5-10% of bc)
4) Radiation exposure (to face or chest before age of 30)
5) Being overweight
6) Early menstruation (before 12)
7) HRT/combined pill

63
Q

What are the symptoms of breast cancer?

A
  • New lump or mass in breast tissue
  • Swelling of all or part of a breast
  • Skin irritation or dimpling
    Breast or nipple pain
  • Nipple retraction
  • Nipple discharge (other than breast milk)
  • Redness, flaking, or thickening of the nipple or breast tissue
64
Q

What are normal breast ducts composed of?

A

Basement membrane and a layer each of luminal epithelial and basal epithelial, also known as myoepithelial, cells

65
Q

Where are the twoareas that uncontrolled proliferation can occur in?

A

ductal (in ducts) or lobular (in lobules)

66
Q

What does hyperplasia mean?

A

Enlargement of tissue due to increased cell division

67
Q

What % of BC are ERalpha+

A

70-80%

68
Q

What happens to ERbeta expression levels in tumour cells?

A

decreased

69
Q

If the BC is ERalpha+ what does this mean about it?

A

Hormone-dependent

70
Q

histopathological sub-classification of invasive ductal carcinoma most commonly depends on what?

A

The expression of ER, PR and HER2 but sometimes consider HER1 and cytokeratins for further classifications

71
Q

ER+ breast cancers are classified as luminal cancers which are divided into what?

A
  • Luminal A – HER2-

* Luminal B – HER2+

72
Q

ER- cancers are ______ or ______ subtypes

A

HER2-enriched

triple-negative

73
Q

What are the genes that familial mutations are associated with breast cancers?
What do these genes do?

A
  • BRCA1 and BRCA2 – key roles in DNA repair and cell cycle
  • ATM – gene underlying ataxia-telangiectasia
  • BARD1 – regulates cell apoptosis
74
Q

How are reast cancers detected?

A

screening (e.g. mammography, MRI) and diagnostic tests (e.g. biopsies) and monitoring tests are used to assess the effect of the treatment

75
Q

Originally, how were ER+ cancers treated?

A

oophorectomy until drugs modulating the oestrogen receptor were developed

76
Q

What drugs have been developed to treat ER+ BC?

A
  • Synthetic steroidal and non-steroidal oestrogens
  • Anti-oestrogens (antagonists)
  • Non-ER-modulating drugs (aromatase inhibitors)
  • Selective oestrogen receptor modulator (SERM)
  • Selective oestrogen down-regulator (SERD)
77
Q

Give an example of a SERM and SERD

A
  • Tamoxifen (SERM)

- Fulvestrant (SERD)

78
Q

How does Tamoxifen work?

A

It’s an antagonist in mammary tissue, induces conformational changes in the ER, but stimulates cholesterol metabolism, bone density and cell proliferation in the endometrium. This was the first targeted anti-cancer therapy for ER+ breast cancer and can reduce the risk of developing breast cancer in high-risk women

79
Q

What are the side effects of Tamoxifen?

A

Hot flushes, bone pain, nausea and fatigue, loss of libido, headache, and increased risk of endometrial cancer

80
Q

How does Fulvestrant work?

A

It prevents ER dimerisation as well as promotes ER degradation and reduces ER expression. It is used to treat advanced and metastatic ER+ breast cancer

81
Q

What are the side effects of Fulvestrant

A

Nausea, vomiting, appetite loss, joint and muscle pain and hot flushes

82
Q

For pre-menopausal women with ER+ BC what treatment is offered? Why?

A

usually administered Tamoxifen with additional GnRH super-agonists, which inhibit oestrogen secretion by suppressing FSH and LH. This is because ovarian oestrogen secretion is the major oestrogen source

83
Q

For post-menopausal women with ER+ BC what treatment is offered? Why?

A 
Aromatase inhibitors (Type I and type II) prevent the conversion of androgens to oestrogens in all tissues
Post-menopausal women generate most of their oestrogen from androgen precursors from the adrenal glands which are made into oestrogen peripherally – such as in the adipose
84
Q

What are the two types of Aromatase inhibitors?

A
  • Type I steroidal inhibitor – exemestane

* Type II non-steroidal inhibitor – anastrozole and letrozole

85
Q

How do Type I aromatase inhibitors work?

A

Type I agents act as irreversible suicide inhibitors

86
Q

How doe type II aromatase inhibitors work?

A

Type II agents are reversible and bind to the haem group in aromatase

87
Q

By what two pathways can tamoxifen resistance work?

A

1) Intrinsic – ER+ or ER- tumour cells with enhanced pre-existing survival pathways
2) Acquired – ER+ tumour cells become tamoxifen resistant through clonal selection

88
Q

Name the 4 resistance mechanisms that can be observed in BC cells

A
  1. ER coactivator and corepressor expression
  2. Growth factor signalling
  3. Androgen receptor expression
  4. ER mutation
89
Q

What is HER2 encoded by?

A

ERBB2

90
Q

What drives the conversion of androstenedione to oestrogens?

A

Aromatisation (of the ‘A’ ring) of testosterone and androstenedione is the final step in the production of oestrogens

91
Q

Where are Aromatase inhibitors expressed?

A

Endoplasmatic reticulum of oestrogen producing cells

92
Q

How does resistance by growth factor signalling work?

A

HER2 and MAPK pathway activation provide survival and proliferation signals independent of ER: These pathways can be activated by overexpression of the receptors or their cognate ligands. Pathway activation can also occur through deregulation of downstream signalling molecules (example: activating mutation in PI3K or loss of expression of PTEN tumour suppressor)

93
Q

How does resistance by androgen receptor work?

A

AR stimulates division in the absence of ER (substitute): AR is expressed in 80-90% of ER+ breast cancers

94
Q

How does resistance by ER mutation work?

A

Constitutive activation of ER even in oestradiol absence following ESR1 mutations

95
Q

How does resistance by coactivation and co-repression work?

A

Overexpression of coactivators (AIB1) and downregulation of corepressors (NCoR) results in Tamoxifen resistance

96
Q

What two ducts are stabilised by androgens?

A

Müllerian duct and Wolffian duct

97
Q

What other hormone does the Wolffian duct require to form?

A

of testosterone secreted from the Leydig cells (at 9 weeks)

98
Q

What is dihydrotestosterone (DHT)?

A

a more potent androgen

99
Q

What does DHT driv?

A

prostate development as well as masculinisation (virilisation) of the external genitalia

100
Q

What is the mullerian duct and how is it repressed in males?

A

the precursor of the female internal reproductive system, by AMH secreted from Sertoli cells

101
Q

What is the prostatic utricle?

A

Remnant of Mullerian duct and forms an indentation in the prostatic urethra

102
Q

What is the Wolffian duct?

A

the precursor of the male internal reproductive system

103
Q

Where is the prostate found?

A

the base of the bladder and encircles the urethra. It is surrounded by a thick, fibrous capsule and its epithelium

104
Q

What is the epithelium of the gut made up of? Describe these cells

A
  • Luminal cells – tall, columnar cells which express cytokeratins 8 and 18, secretory proteins (e.g. PSA) and high levels of AR
  • Basal cells – non-secretory cells which express cytokeratins 5, 14 and p53 with low to absent levels of AR
  • Neuroendocrine cells – rarer cells which produce neuropeptides and other hormones
105
Q

What is prostatic fluid?

A

An alkaline fluid to aid sperm survival and is made up of PSA, zinc, citrate, coagulative enzymes, proteases and polyamines

106
Q

What are the 3 major morbidities associated with the prostate gland?

A
  1. Prostatic hyperplasia
  2. Prostate cancer
  3. Prostatitis (inflammation of prostate)
107
Q

What are the risk factors of Prostate cancer?

A
  • Aging
  • Race – more common in Caucasians
  • Family history
  • Genetic risk
  • Hormone levels in utero
108
Q

What are the symptoms of prostate cancer?

A
  • Frequent urination
  • Poor urinary stream
  • Urgent need to urinate
  • Hesitant urination
  • Lower back pain
  • Blood in the urine
  • Or asymptomatic
109
Q

Most prostate cancers are what type? Originating where?

A

Adenocarcinomas originating in luminal epithelial cells and can be characterised by the absence of the basal cells

110
Q

What is the steps of prostate adenocarcinoma?

A

Intraepithelial neoplasia (PIN), followed by invasive carcinoma and finally castration-resistance and metastasis. The stroma will be altered to support tumour growth.

111
Q

How are prostate cancers classified?

A

using the histopathological Gleason grading system from 1 (normal morphology) to 5 (abnormal morphology with large sheets of epithelium and lost ducts).

112
Q

What genes are associated with prostate cancer? How do they function?

A
  • PTEN – inactivates anti-apoptotic proteins
  • BRCA2
  • ETS fusions – ETS transcription factors and androgen-regulated promoters translocate to produce androgen-driven expression of ETS
  • NKX3.1 – demonstrates haploinsufficiency which initiates prostate carcinogenesis
  • MYC – overexpression during PIN stage drives progression to invasive adenocarcinoma, genome instability and metastasis.
113
Q

How can prostate cancers be detected?

A

digital rectal examination (DRE), PSA test using a blood-sample and antibody-based assay, and ultrasound

114
Q

What does prostate specific antigen (PSA) do?

A

A component of prostatic fluid that normally remains within the ducts as its function is to clear the seminal vesicles clear by lysing seminal coagulate

115
Q

What is the production of prostate specif antigen stimulated by?

A

androgens as it has several androgen-responsive elements in its gene promoter/enhancer regions

116
Q

What are the specific AREs in the PSA gene?

A
  • 170bp upstream of TSS – AGAACA-gca-AGTGCT

* 4000bp upstream of TSS – GGAACA-tat-TGTATC

117
Q

What are normal serum levels of PSA are lower than?

A

4ng/mL

118
Q

Why is there increased levels of prostate specif antigen in the blood serum of patients with prostate cancer?

A

When the barrier in the prostate is disrupted by mechanical disruptions or cell invasion, PSA can escape into the stroma which causes an increased PSA level in blood serum

119
Q

Levels higher than 4ng/ml of PSA in blood serum is indicative of what?

A

carcinoma

120
Q

What amount of PSA is found in advanced disease levels of prostate cancer?

A

100,000ng/mL. This is not the most accurate test and requires biopsy for confirmation of cancer

121
Q

What is the standard care for prostate cancer?

A

Androgen-deprivation therapy (ADT) and seeks to block the androgen pathway

122
Q

How does ADT seek to block the androgen pathway?

A
  • Testicular ablation (i.e. castration)
  • Pituitary down-regulators
  • Anti-androgens
  • Androgen synthesis inhibitors
123
Q

Explain how pituitary down regulators block the androgen pathway?

A

goserelin acetate, buserelin, leuprolide acetate are GnRH agonists that cause an initial increase in LH and testosterone, but the pituitary-gonadal axis is eventually inhibited after 2 weeks. DHT levels are reduced by half, as adrenal androgens can also be converted into DHT

124
Q

Explain how anti-androgens block the androgen pathway?

A

can be steroidal (CPA) which is non-specific or non-steroidal (enzalutamide) which are specific. These induce conformational changes in the AR which reduces its nuclear translocation ability and promotes corepressor binding to the ARE.

125
Q

Explain how androgen synthesis inhibitors block the androgen pathway?

A

Abiraterone is an inhibitor of CYP17 that carries out 2 early steps in androgen synthesis. Knock-on effects on other steroid levels means that patients are required to take glucocorticoids to control blood pressure

126
Q

Resistance o ADT can result in what?

A

castration-resistant prostate cancer (CRPC) or metastatic castration-resistant prostate cancer (mCRPC) and there is no effective treatment for this stage

127
Q

List the resistance mechanisms to ADT

A
  • Loss of ligand-specificity
  • Alternative splice variants (AR-V)
  • AR over-expression
  • Alteration in co-factor levels
128
Q

Explain loss of ligand-specificity as a mechanism for ADT resistance

A

when mutations in the AR-ligand binding domain which increases the sensitivity and decreases the specificity of ligand-binding. This causes inappropriate AR activation.

129
Q

Explain alternative splice variants (AR-V) as a mechanism for ADT resistance

A

of the AR all lack the ligand-binding domain but contain the DNA-binding domain and AF-1, allowing them to be constitutively active

130
Q

Explain AR overexpression as a mechanism for ADT resistance

A

through gene amplification or overexpression causes increased androgen sensitivity in low androgen levels

131
Q

Explain alteration in cofactors levels as a mechanism for ADT resistance

A

can mediate hormone resistance. Increased coactivator levels increase androgen sensitivity whilst increased corepressor levels increase chromatin compaction and inhibit transcription. The ratio of coactivators to corepressors in the target tissue determines the outcome of hormonal treatment

132
Q

Pros and cons of PSA test

A

Inaccurate
False positives
Requires diagnostic biopsy

Non-invasive
Quick/easy
Can just be used for screening
Correlates disease progression and treatment efficiency

133
Q

What is active surveillance of prostate cancer

A

Not taking action on cancer tumour instead watching symptoms

Cancer Biology (10 decks)

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