L26 - Hormone Dependant Cancers: Breast and Prostate Cancer Flashcards
Describe the receptor cell mechanism for steroid hormones?
- steroid hormones cross into the cell cytoplams where they bimd to their receptor
- binding to the receptor causes a conformational change in the nuclear receptor, causing it to become activated (some nuclear receptors 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 resonsive genes are switched on and upregulated
Describe the key characteristics of a nuclear receptor?
LIGAND BINDING DOMAIN:
- binds specific steroid molecules with high afinity
DNA BINDING DOMAIN:
- binds specific DNA sequences
ACTIVATION FUCNTION DOMAIN:
- recruits gene activation machinery, some receptors have a secondary AF2 domain towards the C terminal
Describe the normal morphology of the breast and its function?
The breast is an apocrine gland that produces the milk used 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 organised into 15 to 20 sections called lobes
- within each lobe and smaller structures called lobules where milk is produced
- the milk travels through a network of tiny tubules called ducts. The ducts come together to form larger ducts which eventually exit the skin in the nipple
What are exocrine glands?
secrete substances out onto a surface or cavity via a ductal structure
What are endocrine galnds?
secrete substances directly into bloodstream
What are the 2 mammary gland cell types and what are their structures and functions?
luminal:
- form a single layer of polarised epithelium around ductal lumen.
- produce milk during lactation
Basal:
- comprise the cells that do not touch the lumen
- basally orientated myoepithelial cells in contact with the basement membrane
- have contractile function during lactation
Describe the fucntion of Estrogen in a normal breast?
- drives the expression of genes involved in cellular proliferation and differentiation
- hormone-dependant mammary gland development occurs after puberty each month and results in ductal elongationand triggers side branching
- in an adult, estrogen allows for the maintainance of mammary gland tissue and also primes the tissue fro the effects of progesterone during pregnancy, for milk production
Describe the fucntion of Progesterone in a normal breast?
- increases the branching of the ducts
- prolonged activity in pregnancy leads to more side branching and lactogenic differentiation
What is breast cancer and what are the risk factors for it?
Breast cancer occurs when abnormal cells in the breast begin to grow and divide in an uncontrolled wayand eventually form a tumour
Breast cancer starts int he breast tissu most commonly in the cells that line the milk ducts of the breast
RISK FACTORS:
- age
- lifestyle (smoking and obesity)
- genetic familial factors
Which genes are associated with breast cancer?
women who ahve inherited genetic mutations to certain genes like BRCA1 and BRCA2 are at higher risk of developing breast cancer
How does Reproductive history determine the risk of developing breast cancer?
early onset of menstrual cycle before 12 years and starting menopause after 55 years expose women to hormones longer and are at higher risk of developing breast cancer.
Describe Ductal Breast Carcinoma in Situ (DCIS) as a type of breast cancer?
cancer cells develop within the ducts of the breast but remain within the ducts, it is called DCIS. The cancer cells have not yet developed the ability to spread outside the ducts into the surrounding breast tissue, or to other parts of the body
Describe what Lobular Breast Carcinoma in Situ (LCIS) is?
uncommon condition in which abnormal cells form in the milk glands (lobules) in the breast.
LCIS isn’t cancer however it does indicate an increased risk of developing cancer
Where do the majority of breast cancers arise from and what are the types?
arise from luminal cells. Luminl cells express ER/ Estrogen Receptor.
breast cancer can be ER positive (better prognosis) or ER negative (worse prognosis)
Describe Estrogen in Breast cancer?
- in cancer, the ER signalling pathway is subverted and uncontrolled, which leads to uncontrolled proliferation and differentiation.
- ER’s ability to bind to DNA and open chromatin beocmes hijacked and is used to transcribe many genes, non-coding RNA’s and miRNA’s
- ER then governs cancer cell proliferation and controls and influences many hundreds of genes involved in metastasis, invasion and adhesion
Describe Fulvestrant (Faslodex) as a competitive inhibitor of the ER?
it is an analouge of estradiol.
it competitively inhibitsthe binding of estradiol to the ER receptor with an affinity of 89% that of estradiol.
Fulvestrant and ER binding impairs dimerisation and energy dependant nuleo-cytoplasmic shuttling, thereby blocking nuclear localisation of the receptor
any fulvestrant-E complex that enters the nucleus is transcriptionly inactive as both AF1 and AF2 are disabled
the fulvestrant-ER complex is unstable, resulting in the accelerated degradation of the ER protein
Describe Tamoxifen as a partial agonist of the ER?
binds to ER at the ligand binding site
does not cause the full activation of ER
It can activate ER in the uterus and liver, however it acts as an antagonist in breast tissue
Tamoxifen bound ER does not fold properly and the AF2 domains therefore do not function
Describe aromatase inhibitors as a treatment for breast cancer?
prevents androgens from being converted into estrogen
TYPE 1:
like exemestane
bind irreversibly to aromatase
duration of effect is dependant on the rate of de novo synthesis of aromatase
TYPE 2:
like anastrozole
contain a ring structure that binds the heme iron of cytochome P450 intefering with hydroxylation reactions
What is the main fucntion of the prostate gland?
produces postatic fluid that creates semen when mixed with the sperm produced by the testes
It is an exocrine gland and apocrine gland
What is prostatitis?
inflammation o the prostate gland due to infection
linked to infertility
What are the 2 types of dysregulated growth of the prostate?
Benign = prostatic hyperplasia Malignant = prostate cancer
What are the symptoms of prostate cancer?
- frequent trip to urinate
- poor urinary stream
- urgent need to urinate
- hesitancy wile urinating
- lower back pain
- blood in the urine (rare)
Where does Prostate cancer start and what are the stages of progression?
Starts in the cells that line the lumen - luminal epithelial cells.
Firstly they will hyperproliferate forming prostatic intraepithelial neoplasia (PIN), then they would advance into invasive adenocarcinomas
What are the 3 main ways to detect Prostate cancer?
- digital rectal examination
- PSA test (prostate specific antigen)
- Ultrasound
