Hormone-dependant cancers: Breast cancer

Question 1

what is a hormone?

Answer 1

a chemical messenger that is made by specialist cells, usually within an endocrine gland, and it 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
• thyroid
• thalamus
• Pancreas
• Pituitary
• Adrenal cortex
• testes
  Ovaries

Question 3

How are are the three groups of hormones?

Answer 3

Steroids – lipid soluble small molecules e.g. testosterone
Peptide / proteins e.g. insulin
Modified amino acids / amine hormones e.g. adrenaline

Question 4

what are steroid hormones ?

What receptors do they bind to?

Answer 4

They are small lipophilic molecules, they can easily enter cells by passing through the plasma membrane.

nuclear receptors (effect in the nucleus)

Question 5

what are steroid hormones made from?

what is their basic structure?

Answer 5

cholesterol (either ingested or synthesised de novo in the body)

The basic 4-ring steroid backbone structure

Question 6

Give a brief summary of how corticosteroids and Androgens and Oestrogens are made?

Answer 6

Question 7

examples of steroid hormones

Answer 7

Question 8

what is the role of sex hormones

Answer 8

These are responsible for the sexual dimorphism between males and females,

the development of the secondary sexual characteristics e.g. the growth spurt during puberty, body hair, gonadal development, voice change, breast growth and accessory organs of the reproductive organs e.g. the prostate in men.

Question 9

how do each steroid hormones work systematically

Answer 9

in females oestrogen controls the menstrual cycle, and breast tissue development, fertility, and reproductive organ development, secondary sexual characteristics - body hair etc.

in males testosterone controls reproductive and supportive organs (prostate), development of sexual characteristics in men e.g. deepening of the voice, body hair etc

Question 10

Receptor Mechanism (steroid hormone)

Answer 10

1. Steroid hormones cross into the cell cytoplasm where they will bind to their receptor

2, Binding to the receptor causes a conformational change in the nuclear receptor, causing it to become activated (some nuclear receptor dimerise at this point)

3. Nuclear receptors then translocate into the nucleus
4. Nuclear receptors bind to specific DNA sequences called response elements located in the promoters of steroid responsive genes.
5. Steroid responsive genes are switched on and upregulated.

Question 11

Key Characteristics of Nuclear Receptor

Answer 11

Ligand binding domain (LBD)
Binds specific steroid molecules with high affinity

DNA binding domain (DBD)
Binds specific DNA sequences

Activation function domain (AF1 & 2)
Recruits gene activation machinery, some receptors have a secondary AF2 domain towards the C-terminal

Question 12

what happens when receptors bind steroid hormones

Answer 12

they are activated.
Thus they are called ligand-activated receptors

This causes a physical restructuring of the polypeptide chains in the receptor, activating it

Question 13

Ligand Activated Transcription Factors Process

Answer 13

1. Ligand binding causes a shift in an a-helix, activating the receptor.

2 Receptor dimerises, moves into the nucleus and binds to specific DNA sequences

3. Receptor then recruits DNA modifying enzymes e.g. histone deacetylases, other transcription factors and RNA polymerase to promoters of hormone responsive genes.

Question 14

which domains does the DNA binding domain contain?

Answer 14

The DNA binding domain contains 2 zinc fingers domains, which are essential for sequence specific DNA binding.

Question 15

Hormone Responsive Genes

Answer 15

Many hundreds of genes may be upregulated by a steroid hormone receptor.
Some genes may be downregulated
Genes include functional tissue specific genes, cell cycle and proliferation genes, and genes involved in tissue development and differentiation.

Question 16

Hormone Response Elements

Answer 16

specific DNA sequences found in the promoters of hormone responsive genes.
Many are palindromic

Question 17

Similarity of Steroid Receptors

Answer 17

Receptors have a high homology in the DNA binding domain, and differ in ligand binding domains, and differ significantly in N-terminal activation domains

Question 18

Main Steroid Receptors

Answer 18

Question 19

Describe the morphology of the breast

Answer 19

The breast is anapocrinegland
The breast is composed of glands and ducts
The milk-producing part of the breast is organized into 15 to 20 sections, called lobes.
Within each lobe are smaller structures, called lobules, where milk is produced.
The milk travels through a network of tiny tubes called ducts. The ducts connect and come together into larger ducts, which eventually exit the skin in the nipple.

Question 20

Define exocrine, endocrine and apocrine

Answer 20

The mammary gland is a specialised type of exocrine gland called and apocrine gland.

• Exocrine glands – secrete substances out onto a surface or cavity, via a ductal structure.
• Endocrine glands – secrete substances directly into the bloodstream

Apocrine glands – are a specialised exocrine gland in which a part of the cells’ cytoplasm breaks off releasing the contents.

Question 21

What are the two cell compartments of the mammary gland?

Answer 21

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

Basal – do not touch the lumen, basally oriented myoepithelial cells in contact with the basement membrane, have a contractile function during lactation

Question 22

What are the two major phases in mammary gland development:

Answer 22

hormone-independent from embryonic development up to puberty

hormone-dependent thereafter during puberty, menstrual cycle and pregnancy.

Question 23

ER function in the Normal Breast

Answer 23

Estrogen, together with other hormones (e.g. growth hormone and cortisol) drives the expression of genes involved in cellular proliferation and differentiation

Hormone-dependent mammary gland development occurs after puberty and results in ductal elongation and triggers side branching.

In the adults estrogen allows for the maintenance of mammary gland tissue, and also primes the tissue for the effects of progesterone during pregnancy for milk production.

Question 24

Progesterone Activity In the Normal Breast

Answer 24

Estrogen is primarily involved in the initial growth of breast cancer
The progesterone receptor gene is switched on by the estrogen receptor
Progesterone increases the branching of the ducts
Prolonged progesterone receptor activity i.e. during pregnancy, leads to more side branching and lactogenic differentiation (together with prolactin hormone).

Question 25

What is Breast Cancer? (include lifestyle factors)

Answer 25

when abnormal cells in the breast begin to grow and divide in an uncontrolled way eventually forming a tumour. Breast cancer starts in the breast tissue, most commonly in the cells that line the milk ducts of the breast. 1 in 8 women (approx.) may develop breast cancer in their lifetime. The main risks factors are age, lifestyle (including smoking and obesity), and genetic familial factors.

Question 26

Breast Cancer Aetiology

Answer 26

Age - The risk for breast cancer increases with age. Genetic mutations to certain genes, such as BRCA1 and BRCA2. Women who have inherited these genetic changes are at higher risk of breast and ovarian cancer. Reproductive history. Early-onset of menstrual cycle before 12yrs and starting menopause after 55yrs expose women longer to hormones. Previous treatment using radiation therapy to the chest or breasts (e.g. treatment for lymphoma) before age 30 have a higher risk of getting breast cancer later in life. Not being physically active increases the risk of breast cancer. Being overweight or obese. Taking hormones. Some forms of hormone replacement taken during menopause can raise risk for breast cancer when taken for more than five years. Certain oral contraceptives (birth control pills) also have been found to raise breast cancer risk. Reproductive history. Having the first pregnancy after age 30, not breastfeeding, and never having a full-term pregnancy can raise breast cancer risk. Drinking alcohol. Risk for breast cancer increases with more alcohol.

Question 27

Ductal Breast Carcinoma in Situ (DCIS)

Answer 27

When cancer cells develop within the ducts of the breast but remain within the ducts (‘in situ’), it is called DCIS. The cancer cells have not yet developed the ability to spread outside these ducts into the surrounding breast tissue or to other parts of the body.

Question 28

Lobular Breast Carcinoma in Situ (LCIS)

Answer 28

Lobular carcinoma in situ (LCIS) is an uncommon condition in which abnormal cells form in the milk glands (lobules) in the breast. LCIS isn't cancer. But being diagnosed with LCIS indicates that there could be an increased risk of developing breast cancer.

Question 29

Where do the majority of breast cancers arise from?

Answer 29

luminal cells These cells express ER (oestrogen receptors)

Question 30

ER expression in Breast Cancer

Answer 30

The majority of breast cancers are ER+ve and have a good prognosis, however the remainder are ER-ve and have a relatively poor prognosis. ER-ve breast cancers cannot be treated ‘hormonally’ and patients are given more conventional therapies.

Question 31

ER in Breast Cancer

Answer 31

In the normal breast ER controls functions such as cell proliferation, development and differentiation in a highly controlled manner. However, in breast cancer, the ER signalling pathway is subverted and becomes uncontrolled. ER’s ability to bind DNA and open chromatin becomes hijacked and is used to transcribe many genes, non-coding RNAs and miRNAs. ER then governs cancer cell proliferation, and controls and influences many hundreds of genes involved in metastasis, invasion and adhesion.

Question 32

Targeting ER in Breast Cancer

Answer 32

The mammary gland is an estrogen sensitive and dependent tissue Breast cancer cells retain this sensitivity and dependency – estrogens are a key driver of breast cancer growth. Therefore, this can be used as an inherent vulnerability that can be exploited for treatment. Switch off ER signalling, switch off the the cancer growth. ER targeting is the “Achilles Heel” of breast cancer.

Question 33

Histological Analysis for ER Expression

Answer 33

Question 34

Fulvestrant (Faslodex)

Answer 34

- Fulvestrant is an analogue of estradiol. - competitively inhibits the binding of estradiol to the ER, (binding affinity of 89% estradiol) - This impairs receptor dimerisation, and energy-dependent nucleo-cytoplasmic shuttling, thereby blocking nuclear localisation of the receptor. - fulvestrant – ER complex that enters the nucleus is transcriptionally inactive because both AF1 and AF2 are disabled. - The fulvestrant–ER complex is unstable, resulting in accelerated degradation of the ER protein.

Question 35

Tamoxifen

Answer 35

-Tamoxifen binds the ER at the ligand-binding site. Tamoxifen is a partial agonist but does not cause the full activation of ER. It has a mixed activity – it activates ER in the uterus and liver, but acts as an antagonist in breast tissue. Tamoxifen is a Selective Estrogen Receptor Modulator (SERM). Tamoxifen bound ER does not fold properly and the AF2 domains do not function

Question 36

Tamoxifen Bound ER vs Estradiol bound ER

Answer 36

Estradiol binds deep within a pocket in the receptor and is covered by a loop of the protein chain This loop forms part of the activation signal that will stimulate growth in the cell (AF2). Tamoxifen binds, the extra tail of the drug is too bulky and the receptor loop is not able to adopt its active conformation.

Question 37

Aromatase

Answer 37

When ovaries are no longer functional in postmenopausal women, potential sources of estrogens come from the peripheral conversion of androgens by the aromatase enzyme. This enzyme is present in multiple organs including adipose tissue, brain, blood vessels, skin, bone, endometrium, and breast tissue. Androgens are hormones such as testosterone, or adrenal androgens such as androstenedione

Question 38

Types of Aromatase Inhibitors

Answer 38

Type 1 inhibitors, like exemestane (Aromasin ©), are androgen analogues and bind irreversibly to aromatase, so they are also called “suicide inhibitors”. The duration of inhibitory effect is primarily dependent on the rate of de novo synthesis of aromatase. Type 2 inhibitors, like anastrozole (Arimidex ©), contain a functional group within the ring structure that binds the heme iron of the cytochrome P450, interfering with the hydroxylation reactions.