L26 - Hormone Dependant Cancers: Breast and Prostate Cancer

Question 1

Describe the receptor cell mechanism for steroid hormones?

Answer 1

• 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

Question 2

Describe the key characteristics of a nuclear receptor?

Answer 2

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

Question 3

Describe the normal morphology of the breast and its function?

Answer 3

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

Question 4

What are exocrine glands?

Answer 4

secrete substances out onto a surface or cavity via a ductal structure

Question 5

What are endocrine galnds?

Answer 5

secrete substances directly into bloodstream

Question 6

What are the 2 mammary gland cell types and what are their structures and functions?

Answer 6

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

Question 7

Describe the fucntion of Estrogen in a normal breast?

Answer 7

• 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

Question 8

Describe the fucntion of Progesterone in a normal breast?

Answer 8

• increases the branching of the ducts

- prolonged activity in pregnancy leads to more side branching and lactogenic differentiation

Question 9

What is breast cancer and what are the risk factors for it?

Answer 9

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

Question 10

Which genes are associated with breast cancer?

Answer 10

women who ahve inherited genetic mutations to certain genes like BRCA1 and BRCA2 are at higher risk of developing breast cancer

Question 11

How does Reproductive history determine the risk of developing breast cancer?

Answer 11

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.

Question 12

Describe Ductal Breast Carcinoma in Situ (DCIS) as a type of breast cancer?

Answer 12

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

Question 13

Describe what Lobular Breast Carcinoma in Situ (LCIS) is?

Answer 13

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

Question 14

Where do the majority of breast cancers arise from and what are the types?

Answer 14

arise from luminal cells. Luminl cells express ER/ Estrogen Receptor.

breast cancer can be ER positive (better prognosis) or ER negative (worse prognosis)

Question 15

Describe Estrogen in Breast cancer?

Answer 15

• 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

Question 16

Describe Fulvestrant (Faslodex) as a competitive inhibitor of the ER?

Answer 16

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

Question 17

Describe Tamoxifen as a partial agonist of the ER?

Answer 17

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

Question 18

Describe aromatase inhibitors as a treatment for breast cancer?

Answer 18

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

Question 19

What is the main fucntion of the prostate gland?

Answer 19

produces postatic fluid that creates semen when mixed with the sperm produced by the testes
It is an exocrine gland and apocrine gland

Question 20

What is prostatitis?

Answer 20

inflammation o the prostate gland due to infection

linked to infertility

Question 21

What are the 2 types of dysregulated growth of the prostate?

Answer 21

Benign = prostatic hyperplasia
Malignant = prostate cancer

Question 22

What are the symptoms of prostate cancer?

Answer 22

• frequent trip to urinate
• poor urinary stream
• urgent need to urinate
• hesitancy wile urinating
• lower back pain
• blood in the urine (rare)

Question 23

Where does Prostate cancer start and what are the stages of progression?

Answer 23

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

Question 24

What are the 3 main ways to detect Prostate cancer?

Answer 24

• digital rectal examination
• PSA test (prostate specific antigen)
• Ultrasound

Question 25

What are the stages of Prostate cancer?

Answer 25

T1 = small localised tumour

T2 = palpable tumour

T3 = tumour has escaped from the prostate gland

T4 = local spread to pelvic region

Question 26

What are the treatment options for prostate cancer?

Answer 26

• watchful waiting:
  low grade tumour, older patients
• Radical prostaectomy:
  removal of prostate, stage T1 or T2
• Radical radiotherapy:
  external up to T3, internal implants for T1 and T2
• Hormone therapy:
  with prostatectomy or radiotherapy, metastatic prostate cancer

Question 27

What are some of the risk factors associated with developing Prostate cancer?

Answer 27

• age
• race: more often seen in african-american men and caribbean men. occurs less in asian-americans and latino men
• family history: increased risk if father or brother has it, or if other relatives were diagnosed at a young age.
• diet: men who eat a lot of dairy products have slightly higher risk
• obesity
• chemcial exposures: firefighters can be exposed to certain chemcials that may increase risk of prostate cancer
• inflammation of the prostate
• sexually transmitted infections: may play a role inincreasing the risk of cancer.

Question 28

What are the gene mutatins that are associated with prostate cancer?

Answer 28

• BRCA1 mutations and pten loss

Question 29

Describe inhibition of testosterone synthesis as a treatment for prostate cancer?

Answer 29

if adrenal androgen production can be inhibited, then testes will be deprived of testosterone precursors

Question 30

What does Abiraterone Acetate do?

Answer 30

inhibits the enzymes that are required to convert cholestrol into adrenal androgens

Question 31

What does Finasteride do?

Answer 31

inhibits the action of the 5-alpha reductase enzyme, and therefore prevents testosterone from being converted to DHT

Question 32

What does Bicalutamide do?

Answer 32

compete with testosterone to bind to the AR. It is an antagonist

Question 33

What way can a tumour overcome hormone starvation during treatment of cancer?

Answer 33

• receptor amplification
• ligand binding site mutations: allows other hormones to bind
• receptor phosphorylation/activation
• AR transcripts variants
• antagonists beocme agonists via mutations