Environmental Light and Breast Cancer

Question 1

amount of nm of light to make serotonin, melatonin and vitamin D

Answer 1

• need 480nm to make serotonin (noon sun vs. artificial); melatonin flip side has to be absent 490nm (i.e. light shuts down production/inhibits)
• need 295nm UVB to make vitamin D (so can’t make indoors)

Question 2

what are circadian rhythms

Answer 2

•Physical, mental and behavioural changes that follow a roughly 24-hour cycle, responding primarily to light and darkness in an organism’s environment. They are found in most living things including animals, plants and many tiny microbes.

Question 3

the study of circadian rhythms is called ______

Answer 3

The study of circadian rhythms is called chronobiology

Question 4

light acts on the body by two pathways:

Answer 4

•the primary optic tract governs visual perception and responses whereas the retinohypothalamic tract governs circadian, endocrine and neurobehavioral functions

Question 5

The retinohypothalamic tract is most sensitive to what kind of light

Answer 5

•The retinohypothalamic tract is most sensitive to blue light stimulation energy in the wavelength of roughly 459-485nm

Question 6

light signals through what type of protein and is recieved by what type of cell in back of the eye

Answer 6

•Light signals through melanopsin protein that undergoes a chemical change when exposed to light received by intrinsically photosensitive retinal ganglion cells in the back of the eye

Question 7

Some health effects of circadian clock de-regulation

10 of em

Answer 7

1. Insomnia and sleep disorders
2. Reduced alertness
3. Poor cognitive and motor function
4. Depression, bipolar disorder and seasonal affective disorder
5. Cardio-vascular disease
6. Altered hormone levels
7. Obesity
8. Early-onset diabetes
9. Altered immune function
10. Cancer – breast, prostate and colon

Question 8

what is known as the hormone of darkness and is only secreted at night / is a precursor for serotonin

Answer 8

Melatonin

Question 9

where does melatonin biosynthesis occur

Answer 9

in the pineal gland

Question 10

melatonin is a regulator of what

• rate limiting step
• needs what vitamin

Answer 10

• melatonin is a regulator of ER alpha and estrogen production so clear relationship to breast cancer
• Rate limiting step uses serotonin to make Acetylserotonin
• Need vitamin D in the promoter region of tryptophan hydroxylase

Question 11

what functions does the SCN perform / stimulates what hormones

Answer 11

• Once exposed to the first light each day, the clock in the SCN begins performing functions like raising body temperature and releasing stimulating hormones like cortisol
• The SCN also delays the release of other hormones like melatonin which is associated with sleep onset, until many hours later when darkness arrives

Question 12

day shift vs night shift workers in terms of production of melatonin and serotonin

Answer 12

• Day shift workers who sleep at night have higher levels of melatonin whereas night shift workers had lower levels and its peak production was shifted
• Exposure to light and then darkness is a key factor in melatonin and sleep regulation and it has been recently found that exposure to light at night diminishes melatonin production

Question 13

does melatonin inhibit or excite the estrogen response pathway

Answer 13

melatonin inhibits estrogen response pathway through binding to MT1

Question 14

Melatonin modulated estrogen/ER alpha signalling pathway

Answer 14

• estrogen driven breast cancer and high levels of estrogen / estrogen receptor alpha
• melatonin will bind to a GPCR called mt1 (melatonin 1)
• will modulate effects of estrogen at the estrogen receptor by toning it down and decrease calmodulin actions on phosphorylation, also decreases the amount of estrogen being produced so is modulating aromatase (cells that produce aromatase are in granulosa cells in ovary - androgens produced at cortex can be converted by aromatase including visceral fat maybe surrounding breast) - the presence of melatonin downregulates production of aromatase
• decrease estrogen = decrease proliferation of breast epithelial cells

Question 15

the antiproliferative effects of the melatonin signal are mediated through what mechanism

Answer 15

•the antiproliferative effects of the melatonin signal are mediated through a mechanism involving the activation of melatonin receptors (MT1 a GPCR) expressed in healthy human breast cells and cancer cells

Question 16

what does melatonin suppressed in the estrogen receptor breast cancer cells

Answer 16

•in estrogen receptor (Era+) human breast cancer cells, melatonin supresses both ER alpha mRNA expression and estrogen-induced transcriptional activity of the ER alpha via MT1 induced activation of Gai2 signalling and reduction of cAMP levels

Question 17

the anti-metastatic actions of melatonin involve what

Answer 17

• the anti-metastatic actions of melatonin involve the blockade of both p38 phosphorylation and the expression of matric metalloproteinases
• melatonin also down-regulates growth factor pathways supporting cell proliferation and survival

Question 18

where is serotonin produced and what are it functions

Answer 18

• serotonin is a well-known neurotransmitter but also functions as a hormone
• most serotonin produced in cells of the gut – the remainder is synthesized in the central nervous system where it functions to regulate mood, appetite, memory and sleep
• modulation of serotonin levels is the major action of many antidepressants

Question 19

when are the highest levels of serotonin / need what kind of light

Answer 19

• highest levels in the afternoon; need wavelength of light 480nm – derived from tryptophan (constituent of most protein-based foods)
• need blue light to increase serotonin

Question 20

what is vitamin D essential for and what are other names for it

Answer 20

• vitamin D is essential for the formation of normal bones and teeth by maintaining normal blood levels of calcium and phosphorus but also many important effects including cell differentiation and development
• vitamin D has multiple names – can mean any of the fat soluble vitamins: D1, D2, D3 calcitriol = active vitamin

Question 21

what is vitamin D structrually related to

Answer 21

•structurally related to steroids not a vitamin in this context because uses same type of high affinity nuclear receptor to affect transcription as steroids, and levels regulated (as compared to a vitamin that is typically from a diet and is a cofactor for some protein / enzyme)

Question 22

role of vitamin D in breast cancer (what things does it inhibit)

Answer 22

• Vitamin D inhibits ER alpha and aromatase in the estrogen pathway and COX-2 of the prostaglandin pathway in BOTH cancerous breast epithelial cells and breast adipose fibroblasts surrounding the tumor – this inhibiting breast cancer cell proliferation
• Vitamin D also inhibits proliferation by additional pathways including cell cycle arrest, proapoptotic and prodifferentiation actions, anti-inflammation etc. which are active in both ER+ and ER negative breast cancer cells

Question 23

vitamin D role in breast cancer (4 steps)

Answer 23

1. It induces the expression of cell cycle arrest proteins and pro-apoptotic cell death proteins (Bax and Bak)
2. It supresses inflammation by inhibiting inflammatory enzymes (such as COX-2)
3. It decreases the expression of aromatase, the final enzyme in the synthesis of estrogen by direct repression of transcription via promoter II
4. Also it down regulates the expression of estrogen receptor alpha thus attenuating the estrogen signal that stimulates proliferation

Question 24

breast cancer has been found to be associated with low levels of what 3 things

Answer 24

serotonin, melatonin and vitamin D

Question 25

changes in human exposure to light affects what (4) which increase the risk for chronic disease including breast cancer

Answer 25

• Changes in human exposure to environmental light affects biological rhythms
• Alters the metabolism of key hormones including GnRH, estrogen, progesterone, testosterone, vitamin D and melatonin
• Alters neurotransmitters including dopamine and serotonin
• Alters micronutrients including iron

Question 26

do vitamin D levels follow a circadian rhythm?

• when does concentration of vitamin D peak
• when is it natrually produced

Answer 26

• Figure shows that vitamin D levels also follow a circadian rhythm
• Like serotonin and body temperature the serum concentration of vitamin D peaks after mid-day (highest in late afternon)
• Vitamin D is naturally produced in the body after exposure to sunlight and is a secosteroid hormone (a type of steroid with a “broken” ring) and is produced in the liver

Question 27

wha two things downregulate estrogen signalling and what are the implications for this

Answer 27

• Recall melatonin and vitamin D both downregulate estrogen signalling decreasing breast cancer risk – perhaps low vitamin D leads to low serotonin leading to low melatonin allowing increased estrogen signalling
• Serotonin also has a relationship with breast cancer risk but is less understood at this time