Hormone-dependant cancers: Breast cancer Flashcards
what is a hormone?
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
where are hormones produced?
- pineal gland
- hypothalamus
- thyroid
- thalamus
- Pancreas
- Pituitary
- Adrenal cortex
- testes
Ovaries
How are are the three groups of hormones?
Steroids – lipid soluble small molecules e.g. testosterone
Peptide / proteins e.g. insulin
Modified amino acids / amine hormones e.g. adrenaline
what are steroid hormones ?
What receptors do they bind to?
They are small lipophilic molecules, they can easily enter cells by passing through the plasma membrane.
nuclear receptors (effect in the nucleus)
what are steroid hormones made from?
what is their basic structure?
cholesterol (either ingested or synthesised de novo in the body)
The basic 4-ring steroid backbone structure
Give a brief summary of how corticosteroids and Androgens and Oestrogens are made?
examples of steroid hormones
what is the role of sex hormones
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.
how do each steroid hormones work systematically
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
Receptor Mechanism (steroid hormone)
- 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)
- Nuclear receptors then translocate into the nucleus
- Nuclear receptors bind to specific DNA sequences called response elements located in the promoters of steroid responsive genes.
- Steroid responsive genes are switched on and upregulated.
Key Characteristics of Nuclear Receptor
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
what happens when receptors bind steroid hormones
they are activated.
Thus they are called ligand-activated receptors
This causes a physical restructuring of the polypeptide chains in the receptor, activating it
Ligand Activated Transcription Factors Process
- 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
- Receptor then recruits DNA modifying enzymes e.g. histone deacetylases, other transcription factors and RNA polymerase to promoters of hormone responsive genes.
which domains does the DNA binding domain contain?
The DNA binding domain contains 2 zinc fingers domains, which are essential for sequence specific DNA binding.
Hormone Responsive Genes
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.
Hormone Response Elements
specific DNA sequences found in the promoters of hormone responsive genes.
Many are palindromic
Similarity of Steroid Receptors
Receptors have a high homology in the DNA binding domain, and differ in ligand binding domains, and differ significantly in N-terminal activation domains
Main Steroid Receptors
Describe the morphology of the breast
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.
What are the two cell compartments of the mammary gland?
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
Progesterone Activity In the Normal Breast
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).
Ductal Breast Carcinoma in Situ (DCIS)
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.
Lobular Breast Carcinoma in Situ (LCIS)
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.
Where do the majority of breast cancers arise from?
luminal cells
These cells express ER (oestrogen receptors)
ER expression in Breast Cancer
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.
Histological Analysis for ER Expression
Fulvestrant (Faslodex)
- 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.
Tamoxifen Bound ER vs Estradiol bound ER
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.
Aromatase
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
