24- Hormone Dependent Cancers: SH & Breast Cancer

Question 1

what is a hormone?

Answer 1

chemical messenger made by specialist cells, usually within an endocrine gland, and is released into the bloodstream to have an effect on another part of the body

Question 2

list the three classes of hormones with examples

Answer 2

steroid - e.g. testosterone
peptide/protein - e.g. insulin
modified amino acid/amine - e.g. adrenaline

Question 3

what are the 5 classes of steroid hormone?

Answer 3

androgens
oestrogen
progesterone
corticosteroids
mineralocorticoids

Question 4

what are steroid hormones?

Answer 4

small lipid soluble molecules derived from cholesterol in the adrenal cortex

have a common 4 ring backbone structure

Question 5

describe steroid hormone synthesis - all of them

Answer 5

cholesterol is ingested or synthesised in the body- transported to adrenal cortex where glucocorticoids, mineralocorticoids and the precursors for androgens and oestrogen are synthesised

precursors taken to target gonads - testes for androgen precursors, ovaries for oestrogen precursors

androgen precursor in testes produces testosterone - can undergo further metabolization

oestrogen produced by ovaries

Question 6

describe production and effects of testosterone

Answer 6

production: precursor from adrenal cortex to testes - produced by the testes

controls reproductive and supportive organs like the prostate

promoted development of secondary sexual characteristics - voice deepening body hair growth, pubertal growth spurts

development of male reproductive organs

Question 7

describe the effects and production of oestrogen

Answer 7

production: precursor from adrenal cortex to ovaries -produced by ovaries in females, and in smaller amounts by the male testes and other tissues

controls menstrual cycle

promotes breast tissue development

influences fertility and reproductive organ development

contributed to development of female secondary sexual characteristics

Question 8

describe production and effects of progesterone

Answer 8

production: produced by ovaries in females, during pregnancy, and in smaller amounts in males

involved in menstrual cycle and pregnancy, maintains a suitable environment for a potential embryo

works with oestrogen to regulate female reproductive system

Question 9

describe the relationship between sex hormones and breast & prostate cancer

Answer 9

sex steroid hormones are important in the development of breast & prostate tissue as they’re hormone-dependent tissues

breast cancer involves oestrogen and progesterone - crucial to growth, development and function
= breast cancer therapy involves blocking oest. receptors

prostate cancer involves testosterone and DHT as prostate tissue growth and function requires testosterone
= prostate cancer therapy involves blocking/ reducing action of testosterone

Question 10

list the three main domains of a nuclear receptor

Answer 10

ligand binding domain/ LBD
DNA binding domain/ DBD
activating functional domain/AFD 1& 2 or N-terminal activation binding domain

DBD has high homology within the nuclear receptor superfamily, whereas LBD and AFD vary between each

Question 11

describe the DNA binding domain

Answer 11

contains two zinc fingers - CI and CII - important for sequence specific DNA binding

CI involved in specific DNA sequence binding

CII interacts with the DNA phosphate backbone

Question 12

describe the mechanism for steroid hormones taking effect via nuclear receptors

Answer 12

steroid hormones are small, lipophilic molecules = diffuse through the plasma membrane

bind to their specific intracellular nuclear receptor via the ligand binding domain with high affinity
- shift in alpha helix of nuclear receptor

nuclear receptor is activated, may dimerise - nuclear-steroid complex translocate to nucleus

complex binds to response element - a specific DNA sequence - on the promoter of a steroid responsive gene = upregulates or downregulates gene activity
- response element is often palindromic
- genes up/down regulated - e.g. tissue-specific genes, tissue differentiation or development genes, cell cycle or proliferation genes

receptor recruits DNA modifying enzymes to steroid responsive gene promoter - e.g. RNA polymerases, histone deacetylases, transcription factors

Question 13

describe (tissue) organisation of the breast

Answer 13

breast is an apocrine gland = a specialised exocrine gland which breaks off part of the cell cytoplasm to release its contents

tissue organisation:
breast is in 15-20 lobes - lobes into lobules that produce milk - tiny ducts that transport milk - converge onto larger ducts - eject milk out of nipple

cellular organisation:
surrounding lumen of duct are the luminal/epithelial cells which produce milk during lactation

myoepithelial cells are non-luminal, have a contractile function during lactation

Question 14

describe the stages of mammary gland development and the hormones at play

Answer 14

first stage - hormone independent = from embryonic development to before puberty

second stage - hormone dependent = during puberty, menstrual cycle and pregnancy
- involves oestrogen, progesterone and prolactin and other hormones like growth hormones and cortisol for the growth, development and maintenance of breast tissue

Question 15

how does oestrogen affect hormone dependent breast development?

Answer 15

involved in maintenance of mammary gland tissue in adults

ductal elongation and side branching, hormone terminal end buds

primes tissue for progesterone effects during lactation/pregnancy - oestrogen binding to oestrogen receptors triggers progesterone gene receptor expression

Question 16

how does progesterone affect hormone dependent breast development?

Answer 16

lactogenic differentiation with prolactin

triggers more side branching

extends progesterone receptor activity during pregnancy

Question 17

how does prolactin affect hormone dependent breast tissue development?

Answer 17

lactogenic differentiation with progesterone

alveologenesis

Question 18

what is breast cancer?

Answer 18

abnormal cells in the breast begin to grow and divide in an uncontrolled way, eventually forming a tumour - start in breast tissues, often with cells that line the milk ducts

Question 19

list at least 4/5 factors that increase the risk for breast cancer (8)

Answer 19

age

genetics - mutations in BRCA 1 &2 genes

reproductive history - early onset of menstrual cycle or later menopause = more exposure to hormones

previous radiation therapy

lack of physical activity, being overweight or obese

long-term use of certain hormone replacement therapies during menopause

reproductive factors - e.g. first pregnancy after 30, not having a full-term pregnancy

high alcohol consumption

Question 20

what is ductal carcinoma in situ?

Answer 20

cancer cells confined within the ducts - don’t have the ability to spread beyond the duct or invade other tissues

considered a pre-invasive or non-invasive condition, early detection is important

Question 21

what is lobular carcinoma in situ?

Answer 21

abnormal cells form in the milk glands/ lobules of the breast, contained within tissues - not invasive

isn’t considered a cancer in itself, but indicates an increased risk of developing breast cancer

Question 22

differentiate the types of breast cancer

Answer 22

ER positive - e.g. luminal A, B and HER2+ve cancers
- better prognosis, more common (75%) of breast cancer, can use hormonal therapies to target ER signalling and reduce growth

ER negative - worse prognosis, can’t use hormonal therapies, requires more conventional therapies

Question 23

describe ER signalling in breast cancer

Answer 23

oestrogen binds to ER at LBD - receptor dimerises and translocates into nucleus

complex binds to DNA and recruits proteins for gene transcription - e.g. co-activators, chromatin remodifiers, RNA polymerase

full activation of the receptor occurs when AF 1 & 2 domains are activated = allows for full recruitment of cohort of co-activators

drives normal and cancer cell growth forward, affects DNA binding, opens chromatin and promotes transcription of genes for invasion, metastasis and adhesion

Question 24

list the three main therapies for breast cancer centred around ER signalling

Answer 24

aromatase inhibitors
Fulvestrant
Tamoxifen

Question 25

how does Fulvestrant work in treating breast cancer?

Answer 25

Fulvestrant - competitively blocks oestradiol in ER binding as an analogue

effects:
- inhibits ER dimerization
- when fulvestrant-ER complex translocates to nucleus it accelerates degradation of ER protein
- fulvestrant-ER complex is transcriptionally inactive = no gene transcription = no ER signalling
- doesn’t allow activation of AF 1 & 2 domains

Question 26

how does Tamoxifen work in treating breast cancer?

Answer 26

partial agonist - allows for partial ER activation = only AF1 domain is activated, not AF2

oestradiol binds within a pocket of ER and is covered by a loop of protein chain which is important for activation

Tamoxifen binds at LBD of ER - drug adds too much weight = ER can’t fold properly into its active conformation

conformational change only allows for activation of AF1, not AF2 = partial activity

Question 27

how is Tamoxifen a selective oestrogen receptor modulator?

Answer 27

partial active state of ER stops its activity in breast tissue but not in the uterus or liver

potentially related to the tissue-specific co-activators recruited by activated ERs in these tissues

tamoxifen won’t affect the activity of uterus and liver ERs, affects activity of breast ERs

Question 28

importance of aromatase in oestrogen production?

Answer 28

aromatase converts androgens to oestrogen through hydroxylation (converts oxygen to OH on an aromatic ring)

especially important in post-menopausal women

aromatase enzyme is tissue in many tissue - e.g. bone, skin, endometrium, breast

Question 29

how do the two types of aromatase inhibitors work in treating breast cancer? example of each?

Answer 29

two types of aromatase inhibitors

type 1 - e.g. exemestane - acts as androgen analogue, binds irreversibly to aromatase
- length of inhibitory effect depends on the rate of de novo aromatase synthesis

type 2 - e.g. anastrozole - functional group within structure binds to the haem ion of cytochrome P450, and interferes with aromatase hydroxylation reactions
- can’t hydroxylate androgens to oestrogen

Question 30

example of type 1 aromatase inhibitor

Answer 30

exemestane

Question 31

example of type 2 aromatase inhibitor

Answer 31

anastrozole