Introduction to Hormone-Dependent Cancers (Breast/Prostate) Flashcards
What are hormones?
Hormone = A Chemical messenger produced by specialised cells usually within an endocrine gland and it is released into the bloodstream to have an effect on another part of the body.
Hormones can be chemicals/peptides/proteins
Where are hormones produced? - Endocrine Glands
Brain:
Pineeal gland , Hypothalamus and Pituitary
Thorax:
Thryoid gland and Thymus gland
Abdomen:
Pancreas, Kidney, Adrenal cortex
(stomach,liver,intestines)
Testes (Male)
Ovaries+Uterus (Female)
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How can hormones be classified ?
Steroid hormones - Small, lipid-soluble molecules (testosterone)
Peptide/protein hormones (insulin)
Modified amino acid/amine hormones (adrenaline)
What are steroid hormones ?
Steroid hormones = small, lipid-soluble molecules synthesised from cholesterol in adrenal cortex
All steroid hormones have a basic backbone 4-ring structure (of cholesterol).
Cholesterol is converted to biosynthetic precursors in adrenal cortex
Cholesterol – Adrenal cortex – Gonadal tissues
Outline the process of steroid synthesis
Cholesterol
In the adrenal cortex (secretes primary hormones):
Main corticosteroids and mineralocorticoids synthesised in the adrenal cortex
Androgenic and estrogenic precursors are released into the blood stream (less potent forms of the final hormone)
Gonadal tissues:
Androgens and oestrogens produced in target organs e.g. testes and ovaries take up less potent hormone which produce active hormone (oestrogen, testosterone), then released into the bloodstream
What are some examples of steroid hormones ?
Steroid hormones:
- Androgen (male steroid) - Testosterone
- Estrogen - Estradiol
- Progestogen - Progesterone
- Corticosteroid - Cortisol
- Mineralocorticoid - Aldosterone
What are the sex steroid hormones?
Sex Steroid Hormones
Oestrogen (ovaries), Testosterone (testes).
These are responsible for:
Sexual dimorphism between males and females.
The development of the secondary sexual characteristics :
-Growth spurt
-Body hair growth
-Gonadal development
-Voice change
-Breast growth
-Accessory organs in the reproductive organs -prostate in men
How do steroid hormones work ?
They work systemically, have effects on several tissues simultaneously.
Females - Oestrogen controls menstrual cycle, breast tissue development, fertility, reproductive organ development , secondary sexual characteristics (body hair)
Males - Testosterone controls reproductive organs, supportive organs (prostate), development of sexual characteristics in men (deep voice, body hair)
What is the steroid hormone mechanism of action?
Steroid hormones = Small 4-ringed structure; Lipophilic molecules = easily enter cells by passing through plasma membrane
Once they enter the cell, steroid hormone binds to nuclear receptors; bind in cytoplasm + cause effects in nucleus
- The steroid hormone (lipophilic) circulates in the blood then enters the cell and binds to its nuclear receptor.
- Binding causes a conformational change in the receptor causing it to dissociate from cytoplasmic chaperone proteins and translocate into the nucleus .
- In the nucleus, Steroid-Receptor Complex binds to DNA at specific sequences called Steroid Response Elements (short sequences of DNA found in the promoter region of steroid responsive genes)
- Steroid receptor then functions as a transcription factor and recruits the gene transcription machinery, induces gene expression
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What are the key characteristics of Steroid 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 and 2) - Recruits gene transcription machinery , some receptors have a secondary AF2 domain towards the C-terminal
The same basic domains and structure are shared with many of the major nuclear recpetors
What happens when nuclear receptors bind steroid hormones ?
When these receptors bind steroid hormones they are activated = they are caled Ligand-Activated Receptors
-The binding of steroids to ligand binding domain causes a physical restructuring of the polypeptide chains (conformational change) in the receptor, activating it
What are ligand activated transcription factors ?
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Nuclear R = Ligand Activated Transcription Factor:
Ligand binds to nuclear R = R activates + dimerises + translocates from cytoplasm into nucleus + binds DNA specific sequences (Hormone Response Elements). On the DNA (promoter/Steroid-Responsive Gene), Receptor recruits gene activation proteins+chromatin modifiers to initiate gene transcription
The DNA binding domain contains ………….., which are essential for ……………
- 2 zinc fingers domains
- Nuclear receptor binding to the specific Hormone Reponse Element
4 cysteine residues = sulfur-containing aas, bind to Zinc atom, forming a zinc finger domain. 2 zinc finger domains in close proximity = required for specific DNA binding
1 steroid hormone receptor can ………….. genes
1 steroid hormone receptor can upregulate/downregulate many genes
Genes include functional tissue-specific genes , cell cycle and proliferation genes and genes involved in tissue development and differentiation
What are hormone response elements ?
Hormone Response Elements = Specific DNA sequences found in the promoters of hormone responsive genes.
Palindromic
How does nuclear R bind to DNA Hormone Response Elements?
DNA-Binding Domain of Nuclear R contains zinc fingers which recognise + bind to the specific Hormone Response Elements sequences
What is the Nuclear Receptor Super Family?
- 48 nuclear receptor genes
- Common domain structure
- Activated by ligand binding
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What are the main steroid receptors / ligands and abbreviations ?
- ER - Oestrogen R - oestradiol, oestrone, oestriol
- AR - Androgen R - testosterone, dihydrotestosterone, androstenedione
- PR - Progestagen R - progesterone, pregnenolong
- GR - Glucocorticoid R - cortisol, cortisone
- MR - Mineralocorticoid R - aldosterone
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Nuclear Rs have high homology in which domain?
Nuclear Rs differ in which domain?
DNA-binding domain = high homology
Ligand-binding domain = differ
Which steroid Rs for breast cancer?
Which steroid R for prostate cancer?
Breast cancer Steroid Rs - Oestrogen R (ER) + Progesterone R (PR)
Prostate cancer - Androgen R (AR)
The breast is an……….gland that produces …………..
The breast is composed of …………., which ……………
The milk-producing part of the breast is organized into …………………
Within each lobe are …………………………
The milk travels through ………………..
The ducts ………. and come together into ………….., which eventually ………….
apocrine milk for infants glands and ducts produce the fatty breast milk 15-20 sections (lobes). smaller structures (lobules), where milk is produced. a network of tiny tubes (ducts) connect larger ducts exit the skin in the nipple.
What are apocrine glands ?
The mammary gland is a specialised type of exocrine gland (apocrine gland)
Apocrine glands = specialised exocrine glands in which a part of the cell’s cytoplasm breaks off, releasing the contents
Endocrine glands - secrete substances directly into bloodstream
Exocrine glands - secrete substances out onto a surface via duct
What is exocrine glands ?
Secrete substances out onto a lumen/cavity/surface/onto skin via a duct
What is an endocrine gland ?
These secrete substances directly into the bloodstream
What are the 2 types of glands ?
Exocrine - Duct ,lumen cavity or into skin
Endocrine - Into the blood
What is the mammary gland tissue structure ?
Mammary epithelium consists of 2 cell compartments:
- Luminal - form a single layer of polarised epithelium around the lumen duct, luminal cells produce milk during lactation.
- Basal - the cells that don’t touch the lumen, basally orientated myoepithelial cells in contact with the basement membrane, contract milk outwards during lactation
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What are the 2 major phases in mammary gland (breast) development?
- Hormone-independent - from embryonic development up to puberty
- Hormone-dependent - thereafter during puberty, menstrual cycle and pregnancy
What is the function of oestrogen in the normal breast?
Estrogen (+growth hormone+cortisol) drives the expression of genes involved in cellular proliferation +differentiation of breast
Hormone-dependent mammary gland development occurs after puberty - oestrogen causes ductal elongation + triggers side branching.
In the adult, oestrogen maintains mammary gland tissue + primes the tissue for effects of progesterone during pregnancy - milk production
What is the normal progesterone activity in the normal breast
Oestrogen = primary initial growth of breast cancer
Progesterone receptor gene is switched on by oestrogen receptor.
It increases branching of the ducts
Prolonged activity - leads to more side branching and lactogenic differentiation (prolactin hormone)
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Outline the changes in breast tissue by oestrogen +progesterone +prolactin
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What is breast cancer ?
Breast cancer occurs when abnormal cells in the breast grow + divide in an uncontrolled way and eventually form a tumour
Breast cancer starts in the breast tissue most commonly in the cells which line the milk ducts of the breast
Main risk factors - Age, lifestyle (smoking, obesity), genetic familial factors
What is the Breast Cancer Aetiology ?
Age - Risk ↑ with age - mostly 50+yo
Genetic mutations to certain genes - BRCA1, BRCA2 - genes involving DNA repair. Inherit these mutations = ↑ risk breast+ovarian cancer
Reproductive history - Menstrual cycle <12 years + menopause >55 years = ↑ hormone exposure. First pregnancy 30yo+. Not breastfeeding. No full term pregnancy. ↑ breast cancer risk
Previous treatment using radiation therapy to the chest/breast (e.g.lymphoma) = ↑risk breast cancer
Not physically active
Overweight/Obese
Taking hormones - Hormone Replacement Therapy
Oral contraceptives
Alcohol