Introduction to Hormones and Cancer - Steroid Receptors and Breast Cancer Flashcards
What hormones effect breast cancer?
- estrogen driven
- elevated levels (varies with age and cycles)
- low melatonin
- low vitamin D
What hormones effect prostate cancer?
- testosterone driven
- elevated levels, but controversial
- low melatonin
- low vitamin D
What do prostate cancer and breast cancer have in common?
- both of the hormones involved are anabolic and control growth by interacting with each other
- low melatonin
- low vitamin D
- the hormones involved cycle on a circadian rhythm
What are the four sites of steroid hormone production?
- glands of female breast
- adrenal glands
- ovaries
- testies
What is the adrenal cortex?
- the outside of the adrenal gland
- is of mesodermal origin
- richly vascularized
- produces important hormanes
What can testosterone be converted into?
It can be converted into 17beta-estradiol
- a natural estrogen hormone found in all vertebrates
What is the enzyme that converts testosterone into 17beta-estrodial?
- aromatase
What is estrone?
A form of estrogen that is produced during menopause
What is estradiol?
A predominant form of estrogen in nonpregnant females
What is estriol?
The primary estrogen of pregnancy
What are the seven critical functions of estrogens?
- Essential hormone for development and reproduction
- Present in both men and women, but significantly higher in women
- Promote the development of female secondary sex characteristics
- Stimulates endometrial growth during the menstrual cycle
- Responsible for the maintenance of blood vessels and the skin
- Reduces bone resorption, therefore increasing bone formation
- Increases uterine growth
Which cancers have estrogen and ERs been implicated in?
- breast cancer
- ovarian cancer
- colon cancer
- prostate cancer
- endometrial cancer
Why is estrogen considered the matriarch of GF?
- loss of control due to environmental conditions is a problem
- have a very important role in bone resorption, so if loss -> increase risk in osteoporosis
Why are adipocytes important in breast cancer?
- they express aromatase
- fat is usually a very high functioning endocrine organ
- the produced estrogen is important in the tumor microenvironment
Other than adipocytes, what else produces aromatase?
CAFs
What does it mean when a cancer is considered “ER-positive?”
The estrogen receptors are over expressed
- in about 70% of breast cancer cases
- causes tumorigenesis
What was the first hypothesis proposed to explain why “ER-positive” causes tumorigenesis?
Binding of estrogen to the ER stimulates proliferation of mammary cells, with the resulting increase in cell division and DNA replication, leading to mutations
What was the second hypothesis proposed to explain why “ER-positive” causes tumorigenesis
Estrogen metabolism produces genotoxic effects, such as inhibition of DNA repair pathways and/or toxic metabolites
Why are the hypotheses thought to cause tumor formation?
They are thought to result in:
- disruption of cell cycle
- dysfunctional apoptosis
- dysfunctional DNA repair
What are eight other effects of estrogen?
- Creates proliferative endometrium
- Breast epithelial cell stimulation of proliferation
- Increased body fat and weight gain
- Salt and fluid retention
- Implicated in endometrial cancer
- Increased risk of breast cancer
- Increased risk of prostate cancer
- Restrains bone loss
Why is estrogen necessary in early life?
- necessary for development (eg., cell growth and proliferation of breast tissue)
- necessary for functions related to reproduction (increase in fitness early in life)
- promotes development of breast tissue
- higher levels premenopause
What is estrogen’s role in later life?
- increases breast cancer risk and other ailments later in life
- more cell divisions = more mutations
- lower levels during menopause
What are the steroids bound to in the blood?
Because estrogen and testosterone are not soluble, they are bound by either albumin (38%) or sex hormone binding globulin (SHBG, 60%)
What are nuclear receptors?
- a class of soluble receptors found within cells
- not membrane bound
- bind testosterone and estrogen
- the pathways are relatively slow acting
- remain dormant with heat shock proteins
What is the one exception to the location of the nuclear receptors?
GPCR30 (G protein coupled receptor) binds to estrogen at the membranes
What are the two main families of nuclear receptors?
- Steroid receptors (AR)
- Thyroid receptors (ER and VDR)
- There are also >100 orphan receptors (no known ligand) - Rev-ErbA alpha
Where are the steroid receptors stored and where is the thyroid receptors stored?
Steroid: in the cytoplasm
Thyroid: stored in the nuclease
- an exception is ER
What are hormones for nuclear receptors?
- not proteins
- small (<1kDa) lipophilic/hydrophobic
- can diffuse across the membrane (but TH is known to be transported)
- over 50 in superfamily
What can nuclear receptors bind to?
- Classical hormones (Androgen or estrogen)
- Vitamin D
- Possibly metabolites (bile acids or fatty acids)
Which nuclear receptor homodimerizes and which receptor heterodimerizes?
- Steroid -> homodimerizes
- Thyroid -> heterodimerizes
What is the androgen receptor (AR)?
- male sex
- binds testosterone or dihydrotestosterone
What is VDR?
- Vitamin D receptor
- calcium/phosphorous
- important in development and differentiation
How does estrogen steroid receptor signalling occur?
- Steroid hormone diffuses across the membrane
- Hormone binding releases heat shock protein and exposes the nuclear localization signal
- Dimerization occurs
- Hormone-receptor complex transported into nucleus
- Homorone-receptor complex binds to HRE (specific for whatever hormoneie., ARE, ERE or TRE) and activates transcription eg., could be essential protein for development
How does the thyroid receptor family signalling occur?
- Circulating testosterone bound by SHBG (sex hormone binding globulin)
- Testosterone diffuses or is transported across the membrane
- Either testosterone is reduced to DHT (by 5alpha-reductase) or aromatized to estradiol (E2)
- Activates transcription (can be opposite ie., hormone represses transcription)
- DHT + testosterone bind the same receptor
- AR is always in the cytosol
What is Tamoxifen?
- An antagonist of the estrogen receptor in breast tissue
- It is the usual (anti-estrogen) therapy for ER positive breast cancer in women
What are the four different ways estrogen can interact with ERalpha in the DNA?
- Classical Mechanism
- Non-Direct DNA binding mechanism
- Ligand (E2)-Independent Genomic Action
- Non-genomic mechanism (G protein mediated)
How does the classical nuclear action occur?
- Activation of txn of target gene by E2/ER
- Not activated by antagonist Tamoxifen/ER (Tam inhibits)
- with recruitment of either CoActivators or CoRepressors respectively
How does Non-Classical nuclear action occur?
- ER regulates gene txn on genes without the hormone response element
- interacts with TFs such as SP-1, fos, jun
- E2 binds to ER with the help of coactivators
- AP-1 promoter or other promoting areas that increases the growth of breast epithelial cells
How does Ligand (E2)-Independent Genomic Action occur?
- Growth factors activate Protein Kinase cascades leading to phosphorylation (P) of ER at estrogen response elements
How does Non-genomic mechanism occur?
- G protein mediated
- G protein-coupled estrogen receptor (GPER) E2-GPER mediate estrogen actions from membrane
- phosphorylation caused by GPER
What does the increased GF allow in breast cancer?
Allows for cross talk with ER signalling and is thought to be both a part of the mechanism of breast cancer and endocrine therapy resistance
What is the cross talk between GFs and GF ER due to?
- Due to kinases being able to phosphorylate and alter estrogen receptor alpha activity in a ligand-independent manner
- Phosphorylation may influence ER availability and potential for DNA binding
- Activated by growth factor signalling
What genes are targeted in the Classical Mechanism?
Some genes that fit the paradigm form the Hallmarks of cancer:
- TGF-alpha (upregulated)
- EGF-receptor (upregulated)
- GREB1 (growth regulation by estrogen in breast cancer 1)
- OXT (Oxytocin)
In non-direct DNA binding, how can ERs mediate transcriptions?
- Via tethered interactions through protein-protein interactions
- at Activator Protein-1 (AP-1) and Specificity Protein-1 (Sp-1) sites
In non-direct DNA binding, how can genes be activated?
- by E2 through the interactions of ERs with Fos and Jun proteins at AP-1 binding sites
- eg., upregulating IFG-I, collagenase, and cyclin D1
What is collagenase?
Proteases involved that make cancer metastatically capable
In non-direct DNA binding, what other genes can be activated through this mechanism?
- E2F
- NFKB
What other indirect interactions of ER with DNA can occur in Non-Direct DNA Binding?
With another transcription factor, nuclear factor (NK-kappaB)
