Introduction to Hormone-Dependent Cancers: Breast and Prostate Cancer Flashcards
What is a hormone?
A hormone is 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.
Hormones can be chemicals, peptides or proteins.
Places in the body where hormones are produced include: pineal gland hypothalamus pituitary gland thyroid gland thymus pancreas stomach adrenal cortex kidneys testes ovaries uterus
What 3 classes can hormones be grouped into?
They can be grouped into 3 main classes
Steroids – lipid soluble small molecule e.g. testosterone
Peptide / proteins e.g. insulin
Modified amino acids / amine hormones e.g. adrenaline
What are all steroid hormones synthesised from?
cholesterol which is either ingested or synthesised within the body (contains the basic 4 ringed steroid back bone structure which forms a part of all steroid hormones!)
Cholesterol is converted into pre-cursors and hormones in the adrenal cortex, which is positioned next to the kidney
Where are the main corticosteroids and mineralocorticoids synthesised? What other hormones can be released/what else happens?
What are some examples of steroid hormones?
Main corticosteroids and mineralocorticoids synthesised in the adrenal cortex
Androgenic and estrogenic precursors released into the bloodstream also from the adrenal cortex and reach the Gonadal tissues- Androgens and estrogens produced in target tissues e.g. testes and ovaries – then released into the bloodstream
examples of steroid hormones include: Androgen (testosterone) Estrogen (estradiol) Progestogen (progesterone) Corticosteroid (cortisol) Mineralocorticoid (aldosterone)
in brackets is an example of the group of hormones that is the name above the brackets
What are the sex hormones responsible for?
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.
What effects do steroid hormones have on tissues?
Steroid hormones work systemically, having effects on several tissues
These effects are:
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
What is the action of steroid hormones?
What is the mechanism of the receptor?
Once the steroid hormones enter the cells, they bind to receptors.
These receptors are known as nuclear receptors – as they have their effects in the nucleus, however they may be found in the cytoplasm or nucleus initially.
Steroid hormones are small lipophilic molecules, they can easily enter cells by passing through the plasma membrane.
Mechanism receptor:
Steroid hormones cross into the cell cytoplasm where they will bind to their receptor
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.
What does a nuclear receptor consist of?
1.Ligand binding domain (LBD)
Binds specific steroid molecules with high affinity
2.DNA binding domain (DBD)
Binds specific DNA sequences
3.Activation function domain (AF1 & 2)
Recruits gene activation machinery, some receptors have a secondary AF2 domain towards the C-terminal
When these receptors bind steroid hormones they are activated.
Thus they are called ligand-activated receptors
The binding of steroids to the ligand binding domain causes a physical restructuring of the polypeptide chains in the receptor, activating it
What happens when a ligand binds to a ligand binding site?
Ligand binding to the ligand binding site causes a shift in an a-helix, activating the receptor.
Receptor dimerises, moves into the nuceus 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.
What are the 2 Zinc finger domains found on the DNA binding domain?
The DNA binding domain contains 2 zinc fingers domains, which are essential for sequence specific DNA binding.
1.CI Zinc finger
Specific DNA
sequence binding
2.CII Zinc finger
Interaction with the
DNA phosphate backbone
What are hormone responsive genes and hormone response elements?
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 are specific DNA sequences found in the promoters of hormone responsive genes.
Many are palindromic
What do we know about the nuclear receptor (super)-family?
There are 48 nuclear receptor genes in humans
All share a common domain structure and are thought to arise from a common evolutionary ancestor.
They all share a structure that is activated by ligand binding.
How are steroid hormone receptors similar/different to each other- in which of the 3 parts do they share most in common/differ most?
Receptors have a high homology in the DNA binding domain, and differ in ligand binding domains, and differ significantly in N-terminal activation domains
What do we know about breasts, with regards to structure?
The breast is anapocrinegland that produces themilkused to feed an infant
The breast is composed of glands and ducts, which produce the fatty breast milk.
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 is the difference between an endocrine, exocrine 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
The breast:
Apocrine glands – are a specialised exocrine gland in which a part of the cells’ cytoplasm breaks off releasing the contents.
What 2 cell compartments does the mammary epithelium consist of?
The mammary epithelium consists of two cell compartments:
Luminal – form a single layer of polarized epithelium around the ductal lumen, luminal cells produce milk during lactation.
Basal – comprise of the cells that do not touch the lumen, basally oriented myoepithelial cells in contact with the basement membrane, have contractile function during lactation
Although oversimplified, this constitutes the main mammary gland cell types.
What are the 2 major phases that can be distinguished in mammary gland development?
What do we know about oestrogen and progesterone function in the normal breast?
Two major phases can be distinguished in mammary gland development:
hormone-independent from embryonic development up to puberty
hormone-dependent thereafter during puberty, menstrual cycle and pregnancy.
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 adult estrogen allows for the maintenance of mammary gland tissue, and also primes the tissue for the effects of progesterone during pregnancy for milk production.
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).
What is breast cancer?
Breast cancer occurs when abnormal cells in the breast begin to grow and divide in an uncontrolled way and eventually form 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 are age, lifestyle (including smoking and obesity), and genetic familial factors.
Breast Cancer Aetiology
Age - The risk for breast cancer increases with age; most breast cancers are diagnosed after age 50.
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.
What is Ductal Breast Carcinoma in Situ (DCIS)?
Breasts are made up of lobules (milk-producing glands) and ducts (tubes that carry milk to the nipple), which are surrounded by glandular, fibrous and fatty tissue.
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.
What is 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.
What cells do the majority of breast cancers arise from?
What do these cells express and what are the majority of breast cancers? (in terms of breast cancer subtypes)
The majority of breast cancers arise from the luminal cells.
These cells express ER (estrogen receptor)
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.
What do we know about breast cancer subtypes?
It is an oversimplification to classify breast cancer as either ER+ve or ER-ve.
There are several classifications of breast cancer – approx. 16-20 sub types have been identified based on molecular profiling and are beyond the scope of this module.
ER+ve/PR+ve breast cancer have a better prognosis
Progesterone receptor is in itself an indicator of estrogen activity, but progesterone is becoming a more interesting target for cancer therapy as in some subtypes it may reduce cell growth.
Targeting the Estrogen receptor in breast cancer
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.