Introduction To Hormone Dependant Cancers: Breast And Prostate Cancers

Question 1

What is a hormone?

Answer 1

Chemical messenger made by specialist cells and is released into the bloodstream to have an effect in another part of the body

Question 2

Where are hormones produced?

Answer 2

Pineal gland
Hypothalamus
Pituitary
Thyroid
Thymus
Pancreas
Adrenal cortex

Question 3

What are the three groups of hormones?

Answer 3

Steroids
Peptide/proteins
Modified amino acids/amine hormones

Question 4

What are steroids synthesised from?

Answer 4

Cholesterol

Question 5

Where are the main corticosteroids and mineralocorticoids synthesised?

Answer 5

In the adrenal cortex

Question 6

What are sex hormones responsible for?

Answer 6

Sexual dimorphism between males and females and development of secondary sexual characteristics

Question 7

What are the effects of female sex steroid hormones?

Answer 7

Oestrogen controls the menstrual cycle and breast tissue development, fertility and reproductive organ development

Question 8

What are the effects of male sex steroid hormones?

Answer 8

Testosterone controls reproductive and supportive organs (prostate) and development of secondary characteristics

Question 9

Why are breast/prostate cancer the most commonly diagnosed?

Answer 9

Tissues are hormone dependant

Steroids control several aspects of cellular proliferation, tissue function, gene expression and morphology

Question 10

What is the steroid mechanism of action?

Answer 10

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

Question 11

What are the key characteristics of a nuclear receptor?

Answer 11

Ligand binding domain
DNA binding domain
Activation function domain
Ligand activated

Question 12

What does the ligand binding domain of a nuclear receptor do?

Answer 12

Binds specific steroids with a high affinity

Question 13

What does the DNA binding domain of a nuclear receptor do?

Answer 13

Binds specific DNA sequences

Question 14

What does the activation function domain of a nuclear receptor do?

Answer 14

Recruits gene activation machinery, some receptors have a secondary af2 domain towards the c-terminal

Question 15

What does ligand binding to the ligand binding site cause?

Answer 15

A shift in the alpha helix, which activates the receptor

Question 16

How are hormone responsive genes controlled?

Answer 16

Up or down regulated by steroid hormones

Question 17

What are hormone response elements?

Answer 17

Specific DNA segments found in the promoters of hormone response genes

Question 18

What are hormone response elements made up of?

Answer 18

6 bases, 3 spacer DNA bases, 6 bases

Question 19

How many genes are contained in the nuclear receptor superfamily?

Answer 19

48

Question 20

What do the nuclear receptor superfamily share?

Answer 20

Common domain receptor structure

Question 21

What does the main steroid receptor depend on?

Answer 21

The thing they bind

Question 22

What is the mammary gland tissue composed of?

Answer 22

Glands and ducts that produce fatty breast milk

Question 23

What is the type of the gland that produces milk?

Answer 23

Apocrine gland

Question 24

What is the milk producing part of the breast organised into (and what are they called)?

Answer 24

15-20 sections called lobes

Question 25

What does milk travel through in the breast?

Answer 25

Networks of tiny tubules called ducts

Question 26

What does an exocrine gland do?

Answer 26

Secretes substances out onto a surface or cavity via a ductal structure

Question 27

What does an endocrine gland do?

Answer 27

Secrete substances directly into the bloodstream

Question 28

What is an apocrine gland?

Answer 28

Specialised exocrine gland in which a part of the cell’s cytoplasm breaks off, releasing the contents

Question 29

What is the luminal structure of the mammary gland?

Answer 29

Form a single layer of polarised epithelium and the ductal lumen

Question 30

What do luminal cells produce (And when?)

Answer 30

Milk during lactation

Question 31

What is the basal mammary gland tissue structure?

Answer 31

Comprise the cells that do not touch the lumen and basally orient the epithelial cells in contact with the basement membrane

Question 32

What are the two major phases in mammary gland development and when do they happen?

Answer 32

``` Hormone independant (embryonic -> puberty) Hormone dependant (after puberty) ```

Question 33

What does hormone dependant mammary gland development cause?

Answer 33

Ductal elongation and side branching

Question 34

In an adult what does estrogen allow for in the breast?

Answer 34

Maintenance of mammary gland tissue and primes it for the effects of progesterone during pregnancy for milk production

Question 35

What is the etiology of breast cancer?

Answer 35

``` 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 ```

Question 36

What facets of the reproductive history increase the chance of breast cancer?

Answer 36

Early menstrual cycle onset (<12) | Menopause >55

Question 37

What causes a ductal breast carcinoma in situ (DCIS)?

Answer 37

Cancer developing in ducts and staying there

Question 38

Why do the cancer cells not spread more in DCIS?

Answer 38

Not yet developed the ability to spread

Question 39

What is lobular breast carcinoma in situ?

Answer 39

Abnormal cells form in the milk glands

Question 40

Is lobular breast carcinoma in situ cancer?

Answer 40

No but indicates there could be an increased risk of its development

Question 41

What is the prognosis for estrogen and progesterone receptor positive cancers?

Answer 41

Good

Question 42

What is the prognosis for estrogen and progesterone receptor negative cancers?

Answer 42

Poor

Question 43

How are estrogen and progesterone receptor negative cancers treated?

Answer 43

Hormonally

Question 44

What happens when the estrogen receptor pathway is subverted?

Answer 44

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

Question 45

What is fulvestrant?

Answer 45

Analogue of estradiol

Question 46

How does fulvestrant work?

Answer 46

Competitively inhibits binding of estradiol to the ER, with a binding affinity that is 89% that of estradiol

Question 47

What does the fulvestrant- ER complex do?

Answer 47

Impairs receptor dimerisation and energy dependant nucleo-cytoplasmic shuttling. This blocks nuclear localisation of the receptor

Question 48

How does tamoxifen work?

Answer 48

Binds to the ER at the ligand binding site

Question 49

Is tamoxifen an agonist or an antagonist?

Answer 49

Agonist in uterus but antagonist in breast tissue

Question 50

What happens to tamoxifen bound ER?

Answer 50

Doesnt fold properly and AF2 domains do not function,

Question 51

Where does estradiol normally bind to the ER?

Answer 51

Deep within a pocket in the receptor

Question 52

What happens when estradiol binds to ER?

Answer 52

Covered by a loop of protein chain, which is its active configuration

Question 53

How does tamoxifen affect the binding of estradiol to the ER?

Answer 53

Binds to the chain that covers bound estradiol cauing it to be too bulky to cover it, so it cant adopt its active conformation

Question 54

Where does estrogen come from in post-menopausal women?

Answer 54

Peripheral conversion of androgens by blood vessels

Question 55

Where is the aromatase enzyme present?

Answer 55

Adipose tissue, brain, blood vessels, skin, bone, endometrium and breast tissue

Question 56

What is a type 1 aromatase inhibitor?

Answer 56

Exemestane | Androgen analogue that binds nearby to aromatase

Question 57

What is an example of a type 1 aromatase inhibitor?

Answer 57

Exemestone

Question 58

What is the duration of type 1 aromatase inhibitor effect dependant on?

Answer 58

Rate of de novo aromatase synthesis

Question 59

What is an example of a type 2 aromatase inhibitor?

Answer 59

Mastozole

Question 60

What do type 2 aromatase inhibitors contain?

Answer 60

Functional group within the ring structure that binds to the haem iron of cytochrome P450

Question 61

What is the main function of normal prostate gland tissue?

Answer 61

Produce prostatic fluid that creates semen when mixed with the sperm produced by the testes

Question 62

What type of gland is a prostate gland?

Answer 62

Exocrine

Question 63

What are the steps in prostate development?

Answer 63

Hormone independant (embryo->puberty) Englargement during puberty Hormone dependant maintenance in adulthood Reactivation of prostate growth in old age

Question 64

What is prostatitis?

Answer 64

Prostate inflammation due to infection

Question 65

What are the two types of dysregulated prostate growth?

Answer 65

Benign - benign prostatic hyperplasia | Malignant - prostate cancer

Question 66

What are the symptoms of prostate cancer?

Answer 66

``` Frequent urination Poor urinary stream Urgent need to urinate Hesitancy while urinating Lower back pain Blood in urine ```

Question 67

Where does prostate cancer start?

Answer 67

Luminal epithelium tissues

Question 68

What does hyperproliferation of the luminal epithelium cause?

Answer 68

Prostate intraepithelial neoplasia

Question 69

How can prostate cancer be detected?

Answer 69

Digital rectal examination PSA test (prostate antigen blood test) Ultrasound

Question 70

What are the classes of prostate cancer?

Answer 70

T1-4, N0-3, M1a-c

Question 71

What is a T1 tumour?

Answer 71

Small localised tumour

Question 72

What is a T2 tumour?

Answer 72

Palpable tumour

Question 73

What is a T3 tumour?

Answer 73

Escape from prostate gland

Question 74

What is a T4 tumour?

Answer 74

Local spread to pelvic region

Question 75

What is a N0 tumour?

Answer 75

No cancer in any lymph nodes

Question 76

What is a N1 tumour?

Answer 76

One positive lymph node <2cm big

Question 77

What is a N2 tumour?

Answer 77

>1 positive lymph node or one 2-5 cm big

Question 78

What is a N3 tumour?

Answer 78

Any positive lymph node >5cm across

Question 79

What is a M1a tumour?

Answer 79

Non-regional lymph nodes

Question 80

What is a M1b tumour?

Answer 80

Bone

Question 81

What is a M1c tumour?

Answer 81

Other sites

Question 82

What is the gleason grading system used for?

Answer 82

To help evaluate the prognosis of men using prostate biopsy samples

Question 83

What are the stages in the gleason grading system?

Answer 83

``` 1- small, uniform glands 2- more stroma between glands 3- distinctly infiltrative margins 4- irregular masses of neoplastic glands 5- only occasional gland formation ```

Question 84

What are the treatments for prostate cancer?

Answer 84

Watchful waiting Radical prostatectomy Radical radiotherapy Hormone therapy

Question 85

What are the risk factors for prostate cancer?

Answer 85

``` Age Ethnicity Family history Inherited BRCA1/2 gene Men with lynch syndrome Diet Obesity Chemical exposures Inflammation of the prostate STIs ```

Question 86

What is pten?

Answer 86

Phosphatase that antagonises the phosphatidylinositol 3-kinase signalling pathway

Question 87

What does loss of pten result in?

Answer 87

Increased growth function signalling

Question 88

How does TMP-RSS2 ERG fusion cause prostate cancers?

Answer 88

Androgen receptor drives proto-oncogene ERG which leads to inappropriate gene activation

Question 89

What does abiratrone acetate do?

Answer 89

Inhibits testosterone synthesis in the adrenal gland

Question 90

What are finasteride and dutasteride?

Answer 90

5 alpha reductase inhibitors

Question 91

What are some examples of anti-androgen drugs?

Answer 91

Bicalutamide Enzalutamide Flutamide Nilutamide

Question 92

What are 5 alpha reductase inhibitors commonly used for?

Answer 92

Benign prostate hyperplasia

Question 93

What happens to hormone therapies over time?

Answer 93

Become less and less effective because cells develop mechanisms to overcome hormonal starvation

Question 94

What kind of mechanisms can tumours develop to overcome hormonal starvation?

Answer 94

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