Breast cancer is the leading cause of death from cancer among women, accounting for 23% of the total cancer cases and 14% of cancer deaths in 2008. As dietary fat is thought to be one of the main risk factors, this webinar will focus on the opposing effects of the omega-6 fatty acid arachidonic acid (AA) and the omega-3 fatty acid eicosapentaenoic acid (EPA) on factors related to breast cancer risk, development and prognosis, including their influence on cyclooxygenase activity and prostaglandin production, the impact of inflammation within the tissue microenvironment, impact on aromatase and oestrogen production and impact on genetic aspects of breast cancer such as modulation of BRAC1 and BRAC2 genes.

1. Fatty acids and breast cancer
Dr Nina Bailey
BSc MSc PhD ANutr

2. Common cancers (males vs females) UK, 2010
25%
31%
47%
46%
14%
Prostate
Breast
12%
Lung
14%
Bowel
Other sites
http://www.cancerresearchuk.org/cancer-info/cancerstats/incidence/commoncancers
11%
Lung
Bowel
Other sites

3.  Breast cancer is one of the most commonly diagnosed cancers and the
leading cause of death from cancer among women,
 Breast cancer accounted for 31% of the total cancer cases in 2010
 Risk factors:
Gender
Hormones
Aging
Reproductive history
HRT/birth control
Breast density
Genetic risk factors
Family history
Alcohol consumption
Obesity
Sedentary lifestyle
Dietary factors

4. Diet and lifestyle
 For the past few decades, epidemiological studies have suggested
that a healthy diet and lifestyle is critical for the prevention of breast
cancer
 For women living in low-risk countries, the risk of developing breast
cancer increases upon immigration to a high-risk country (exposure to
Western lifestyle), which suggests that this cancer is influenced by
modifiable lifestyle or environmental factors (Ziegler et al., 1993)
 Dietary fat is one of the most intensively studied dietary factors
closely related with risk

5. Dietary fat
 Dietary fat is thought to be one of the main risk factors, on the basis of reports
of positive correlations between dietary fat intake and increased risks for cancers
of the breast, colon and prostate
 Epidemiological and in particular experimental studies have shown the link
between dietary fat and breast cancer (Rose 1997)
 The effect of a high fat diet on the risk of breast cancer may not be as
important as the effect of the different kinds of dietary fat, including
saturated, monounsaturated and polyunsaturated fat
 Evidence suggests that the polyunsaturated fatty acids affect breast cancer
proliferation, differentiation and prognosis
 The omega-6 to omega-3 ratio

6. •
•
•
•
Cell fluidity
Metabolism
Growth and development
Brain structure and function
• Eicosanoid production
 Immunity
 Cardiovascular health
 Inflammation
• Cell cycle control

7. AA, EPA and the cell cycle
 A high rate of cell proliferation rate and a low rate of apoptosis are
the hallmark of abnormal cell growth
 AA and EPA have opposing effects on the
proliferation, differentiation and apoptosis of genetically altered cells
and therefore the disposal/accumulation of DNA damaged tissue
(Cathcart et al, 2011)
 The antiproliferative effects of EPA combined with the ability to
induce programmed cell death suggests that E-EPA supplementation
may have a significant impact on halting disease progression
(Hawcroft et al., 2010; Hawcroft et al., 2012)

8. A new biomarker in cancer patients: the AA to EPA ratio
 Aim To evaluate the potential value of tumour risk assessment in colon and breast
cancer patients by determining the AA to EPA ratio in plasma in a case-control study
against healthy patients (Garassino et al., 2006)
 Findings
Colorectal cancer
AA/EPA ratio was 22.232+1.852 compared to 14.25+1.083 for healthy
subjects (median age 70; range 53 - 81)
Breast cancer
The AA/EPA ratio was 21.029+2.584 compared to 12.10+1.414 in healthy
subjects (median age 77; range 44 - 86)

9. Cancer – an inflammatory disease?
 The link between non-resolving inflammation and cancer is well
documented, with epidemiological evidence supporting that approximately 25%
of all human cancer worldwide is caused by non-resolving inflammation
 Inflammatory cells are found in the microenvironment of most, if not all
tumours
 High AA content of cells indicates a pro-inflammatory microenvironment
 Products derived from inflammatory cells influence almost every aspect
of cancer
Vendramini-Costa & Carvalho 2012

10. Inflammatory response
Resoleomics - the process of inflammation resolution
Eicosanoid switch
Stop signal
Pro-inflammatory reduced
LTB4
PGE2
Anti-inflammatory increased
Time
Initiation
Resolution
Bosma-den Boer et al., 2013
Termination

11. Inflammation and omega-3 & omega-6 fatty acid intake among
breast cancer survivors
The Health, Eating, Activity and Lifestyle Study (HEAL)
Investigated the correlation between inflammation and fatigue and the
intake of omega-6 and omega-3 PUFAs among breast cancer survivors
 Six hundred thirty-three particiants (mean age, 56 years; stage I to IIIA)
 Higher intake of omega-6 relative to omega-3 PUFAs was associated with
higher levels of the inflammatory marker C-reactive protein
 Survivors with the highest C-reactive protein had the highest levels of
fatigue
Alfano et al., 2012

12. Inflammation and tumour development
 Inflammation causes cellular stress and may trigger DNA damage or
genetic instability
 Chronic inflammation may contribute to primary genetic mutations
leading to malignant cell transformation
 Inflammation has an important role in all phases of tumour
development:
• Initiation
• Promotion
• Invasion
• Metastatic dissemination
 Thus, suppression of pro-inflammatory pathways may provide
opportunities for both prevention and treatment of cancer

13. Phospholipid
Phospholipase A2
Arachidonic acid
COX-1
COX-2
PGH2
PGD2 PGE2 PGF2
PGI2

14. The role of COX
 Before the discovery of COX-2 it was known that prostaglandin synthesis
could be stimulated by a variety of substances including cytokines, growth factor
and tumour promoters
 These effects were due to activation of phospholipases which supply
arachidonic acid to COX
 The two COX enzymes are regulated independently:
COX-1 is constitutively expressed
COX-2 is inducible and expressed only in response to certain stimuli
 COX-2 is over-expressed in cancer

15. Arachidonic acid
COX-1
COX-2
Constitutive
‘gate-keeping functions’
Induced
Homeostatic function
Gastrointestinal tract
Renal tract
Platelet function
Macrophage differentiation
Inflammation

16. COX-2 over-expression plays an important role in the pathogenesis of
malignant breast cancer in humans
COX-2 plays a key role in tumourigenesis through
•
•
•
•
•
•
stimulating epithelial cell proliferation
inhibiting apoptosis
stimulating angiogenesis
enhancing cell invasiveness
mediating immune suppression
increasing the production of mutagens
Singh-Ranger et al., 2002

17. COX-2 expression in aggressive breast cancer
HER-2 (human epidermal growth factor 2)
 Over-expression (HER-2/neu-positive) of this gene has been shown to play an
important role in the development and progression of certain aggressive types
of breast cancer (15-30% of breast cancers)
 Strongly associated with increased disease recurrence and a poor prognosis
 Of 29 micro-dissected breast cancers:
high levels of COX-2 protein in 14 our of 15 (93%) HER-2/neu-positive samples
high levels of COX-2 protein in 4 our of 14 (29%) HER-2/neu-negative
tumours
Subbaramaiah et al., 1999

18. COX-2 expression and breast cancer prognosis
 Cancer group: 57 primary breast cancer patients
Control group: 27 patients consisting of fibro-adenoma and benign breast disease
 Control group COX-2 was over-expressed in 0%
Cancer group COX-2 was over-expressed in 74% breast carcinoma patients
 COX-2 expression is directly correlated with ER negative (88.1%, p = 0.001) and also
associated with higher NPI value (78.6%, p = 0.006).
 COX-2 over-expression was found to correlate with aggressive phenotypic
features, such as high histological grade, large tumour size, higher NPI value, ER
negativity and HER-2/neu positivity
Jana et al., 2012

19. COX-2, aromatase and oestrogen
 About 75% of breast cancers are ER positive
 Oestrogens are produced from androgens by the action of the enzyme aromatase
 In postmenopausal women, plasma oestrogens result from peripheral
aromatisation, particularly in adipose tissue
 Many breast cancers, also contain aromatase with certain breast cancers able to
synthesise oestrogens by intratumoural aromatase activity
 COX-2 expression has been found to correlate with aromatase expression within
human breast cancer tissue
 Inflammation is a major activator of aromatase activity
Brueggemeier et al., 2006

20. Arachidonic acid
COX-1
COX-2
Constitutive
‘gate-keeping functions’
Induced
Homeostatic function
Gastrointestinal tract
Renal tract
Platelet function
Macrophage differentiation
Inflammation
Cancer
Block

21. Women’s Health Initiative (WHI) Observational Study designed to address
some of the major causes of morbidity and mortality in an ethnically and
geographically diverse sample of postmenopausal women
Examined the effects of regular use of aspirin, ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) on breast cancer risk
 21% decrease in the risk of breast cancer among women who took NSAIDs
at least twice a week for at least 5 years
 28% decrease in the risk for women who used them for at least 10 years
 statistically significant inverse linear trend of breast cancer incidence with
the duration of NSAID use (P < 0.01)
Harris et al., 2003

22. Data from 91 epidemiological studies examined the dose response of relative
risk and level of NSAID intake for ten human malignancies
 Results showed a significant exponential decline in the risk with increasing
intake of NSAIDs (primarily aspirin or ibuprofen) for 7-10 malignancies
 Daily intake of NSAIDs, primarily aspirin, produced risk reductions of 63%
for colon, 39% for breast, 36% for lung, and 39% for prostate cancer
 Significant risk reductions were also observed for oesophageal
(73%), stomach (62%), and ovarian cancer (47%)
 NSAID effects became apparent after five or more years of use and were
stronger with longer duration
Harris et al., 2005

23. Use of COX-2 inhibitors and breast cancer risk
Meta-analysis of 6 cohort studies (number of cases ranged from 14 to 2414) and 8
case-control studies (number of cases ranged from 252 to 5882)
(Khuder & Mutqi 2001)
• Regular use of NSAID associated with 18% reduced risk of breast cancer
Meta-analysis of 38 studies (16 case-control studies, 18 cohort studies, 3 casecontrol studies nested in well-defined cohorts, and 1 clinical trial) that included
2,788,715 subjects
(Takkouch et al., 2008)
• Regular use of aspirin associated with 13% reduced risk of breast cancer
• Regular use of ibuprofen associated with 21% reduced risk of breast cancer

24. Use of COX-2 inhibitors and breast cancer risk
Meta-analysis of 26 studies with 528,705 participants
(Zhao et al., 2009)
• Regular use of aspirin associated with 17% reduced risk of breast cancer
• Regular use of ibuprofen associated with 19% reduced risk of breast cancer
Meta-analysis of 33 studies (19 cohort studies, 13 case-control studies, and 1
randomized controlled trial ) that included 1,916,448 subjects
(Luo et al., 2012)
• Regular use of aspirin associated with 14% reduced risk of breast cancer

25. COX-2
Aromatase
Prostaglandin
COX-2 inhibitor
Angiogenesis
Oestrogen
Facilitation of tumour growth
Oestrogen dependant growth

26. Selective vs non-selective NSAIDS
 Non-selective NSAIDs block both COX-1 and COX-2 [aspirin, ibuprofen
(Brufen, Nurofen), naproxen (Naprosyn), diclofenac (Voltarol), etodolac
(Lodine), and meloxicam (Mobic)]
 Duel acting NSAIDS (COX/5-lipoxygenase inhibitors) [tepoxalin
(Zubrin), meloxicam (Metacam)]
 Selective COX-2 inhibitors – ‘coxibs’ [celecoxib (Celebrex), etoricoxib (Arcoxia)]
 Main side effects associated with NSAIDs
 gastrointestinal and renal effects (Lanas & Ferrandez 2013)
 increased risk of heart attack, stroke heart failure or other thrombotic
events or cardiovascular complications (Fanelli et al., 2013)

27. Selective COX-2 inhibitor drugs still have side effects
 Merck & Co withdraws Rofecoxib (Vioxx, Vioxxacute) in September 2004
because evidence of an increased risk of confirmed serious thrombotic
events (including myocardial infarction and stroke) compared to
placebo, following long-term use
 Pfizer withdraws Valdecoxib (Bextra) from the EU market in April 2005
because serious and potentially fatal skin reaction associated with its use
outweighed the benefits
 What are the non- pharmacutical alternatives?

28. Arachidonic acid
EPA
COX-1
COX-2
Constitutive
‘gate-keeping functions’
Induced
Homeostatic function
Gastrointestinal tract
Renal tract
Platelet function
Macrophage differentiation
Inflammation
Cancer
EPA

29. The role of EPA as a competitive inhibitor
High arachidonic acid
levels
COX-2
Pro-inflammatory ‘cancer
driving’ prostaglandins
Increased EPA lowers
arachidonic acid levels
COX-2
Anti-inflammatory
‘cancer-suppressing
prostaglandins
Increased EPA lowers
arachidonic acid levels
EPA competes with AA
for COX-2
Anti-inflammatory
‘cancer-suppressing
prostaglandins

30. Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast
cancer: meta-analysis of data from 21 independent prospective cohort studies
 Twenty six publications, including 20,905 cases of breast cancer and 883,585
participants from 21 independent prospective cohort studies were eligible
• 11 articles (13,323 breast cancer events and 687,770 participants)
investigated fish intake
• 17 articles investigated marine n-3 PUFA (16,178 breast cancer events and
527,392 participants)
• 12 articles investigated ALA (14,284 breast cancer events and 405,592
participants)
Zheng et al., 2013

31. Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast
cancer: meta-analysis of data from 21 independent prospective cohort studies
 Main findings:
• No significant association was observed for fish intake or for short-chain
omega-3 ALA intake
• Marine omega-3 PUFA was associated with 14% reduction of risk of breast
cancer (relative risk for highest v lowest category 0.86 (95% confidence interval
0.78 to 0.94), I(2)=54)
• Dose-response analysis indicated that risk of breast cancer is reduced by 5%
per 0.1g/day increment of dietary marine n-3 PUFA intake
Zheng et al., 2013

32. Fish consumption patterns
•
•
•
•
•
Type (oily vs white; farmed vs wild)
Omega-3 content/omega-6 content
EPA to DHA ratio
Cooking method
Frequency of consumption
Welch et al., 2002
Cod
Tuna
Salmon
Haddock
Plaice
Herring
Mackerel
29.9%
16.4%
14.2%
13.0%
7.6%
6.0%
3.0%

33. Dietary polyunsaturated fatty acids and breast cancer risk in Chinese women:
a prospective cohort study (Shanghai Women’s Health Study) (Murff et al., 2011)
 72,571 cancer free woman at recruitment (1996 to 2000) with 712 cancer cases reported at
follow-up (2007)
 Women who consumed the highest levels of omega-6 with the lowest amounts of marine
derived omega-3 had 2-fold increased risk for breast cancer compared to women consuming
the lowest amounts of omega-6 and highest amount of omega-3 PUFA intake
 There was a statistically significant interaction between total omega-6 intake, marine-derived
omega-3 intake and breast cancer risk

34. Specialty supplements and breast cancer risk in the VITamins And Lifestyle
(VITAL) Cohort
 Postmenopausal women (n = 35,016) recruited 2000-2002
 Incident invasive breast cancers (n = 880) from 2000 to 2007
 Data on supplement use (current versus
past), frequency (days/week), and duration
(years)
 Current use of fish oil was associated with a
32% reduced risk of breast cancer with a
ten-year average use suggestive of
reduced risk (P trend = 0.09)
Brasky et al., 2010

35. •
Dietary intake of specific fatty acids and breast cancer risk among postmenopausal
women in the VITAL cohort
 Association between fatty acid intake and breast cancer risk (diet and supplements)
 Total SFA was suggestive of an increased risk (HR = 1.47, 95% CI: 1.00-2.15, P = 0.09)
 Total PUFA intake was not associated with increased risk of breast cancer risk (HR =
0.84, 95% CI: 0.65-1.09, P = 0.27)
 Intake of eicosapentaenoic (HR = 0.70, 95% CI: 0.54-0.90, P = 0.04) and docosahexaenoic
acid (HR = 0.67, 95% CI: 0.52-0.87, P = 0.01) were inversely associated with risk
Sczaniecka et al., 2012

36. Modulating eicosanoids
 Products (eicosanoids) derived from AA and EPA play a central role in
inflammation and tissue homeostasis, and are directly implicated in cancer
 Chronic inflammation is one of the foremost risk factors for different types of
malignancies, including breast cancer
 Inflammation in the tumour microenvironment is now recognised as one of the
hallmarks of cancer
 Regulating eicosanoid production may serve as a method to reduce risk as well as
serve as a therapeutic target for inhibiting tumour growth

37. Modulation of angiogenesis by AA and EPA
The formation of new blood vessels (angiogenesis), a critical process that affects
tumour growth and dissemination (Szymczak et al., 2008)
 EPA inhibit and AA stimulates major pro-angiogenic processes in human
endothelial cells:





angiopoietin-2 (Ang-2)
vascular endothelial growth factor (VEGF)
basic fibroblast growth factor (bFGF)
insulin-like growth factor-1
matrix metalloproteases (MMPs) that degrade the extracellular
matrix, and play an important role in the migration of endothelial cells
during angiogenesis

38. BRCA (breast cancer susceptibility protein) genes
 BRCA1 and BRCA2 are human genes that belong to a class of genes
known as tumour suppressors
 As human caretaker genes they produce a protein responsible for
repairing DNA or destroying cells if DNA cannot be repaired
 Mutations in BRCA1 and BRCA2 damaged DNA is not repaired properly
and this increases risks for cancers

39. Omega fatty acids and BRCA genes
 EPA in vitro has been shown to mediate gene expression in human cells
 AA down-regulates BRCA1 and BRCA2 expression which increases
proliferation and anchorage independent growth of tumour cells
 EPA increases BRCA1 and BRCA2 expression which decreases
proliferation and increases apoptosis of tumour cells
Bernard-Gallon et al., 2002

40. Arachidonic acid and eicosapentaenoic acid metabolism contribute to cancer
risk and progression through pro-and anti-inflammatory lipid metabolites that
stimulate cell proliferation, angiogenesis, and migration
Azrad et al., 2013

41. EPA and cancer cachexia
 Cachexia is a form of muscle wasting often associated with advanced stage
cancer
 Inflammatory cytokines appear to tilt the body's metabolism toward
catabolism, the breakdown of muscle proteins and fat ultimately lead to a
chronic state of wasting and malnourishment
 Cachexia is a complication responsible for around 20% of cancer deaths
 EPA supplementation decreases weight loss, promotes weight gain and
increases survival times in patients affected with cancer cachexia
 (Kanat et al., 2013)
 Not all intervention studies show improvements and EPA supplementation
may be more effective if provided earlier rather than later, when muscle
loss is accelerated
(Murphy et al., 2011)

42. GLA and breast cancer
 GLA is metabolised to DGLA to produce anti-inflammatory eicosanoids
 Addition of GLA to EPA reduces accumulation of AA (Barham et
al., 2000)
 GLA has a number of anti-tumour properties:
 GLA reduces the secretion of SPARC and Ang-1 and inhibits the
growth and metastasis of a variety of tumour cells (Cai et
al., 1999; Watkins et al., 2005)
 GLA significant reduces tumour ER expression and enhances
tamoxifen efficacy in human breast cancer cells (Kenny et
al., 2000)

43. EPA and breast cancer
 EPA displaces AA and reduces the production of inflammatory products

EPA blocks the activity of cyclooxygenase-2 (COX-2) and the production of
prostaglandin E2 (PGE2) inhibiting tumourigenesis

EPA reduces the production of pro-inflammatory cytokines TNF- , IL- 1

EPA increases BRCA1 and BRCA2 expression, inhibits proliferation and
induces apoptosis (programmed cell death)

EPA down-regulates aromatase activity and decreases oestrogen production

EPA inhibits major pro-angiogenic processes

EPA may have potential in the treatment of cancer cachexia

Combining EPA with GLA offers synergistic benefits

44. AA and breast cancer


AA gives rise to key pro-inflammatory mediators involved in orchestrating
cross-talk between tumour epithelial cells and immune cells
AA drives inflammation within the tumour environment

Cyclooxygenase-2 (COX-2) is an enzyme over-expressed in many human
cancers and converts AA to prostaglandin E2 (PGE2), which drives
tumourigenesis

AA down-regulates BRCA1 and BRCA2 and promotes the
proliferation, migration and invasiveness of cancer cells

AA stimulates aromatase activity and increases oestrogen production

AA stimulates major pro-angiogenic processes

45. Shifting the balance
 AA and EPA content of cell membranes can be altered through
consumption of omega-3 EPA (marine products/marine oils)
 Changing the fatty acid composition of cell membranes affects
• changes in membrane structure
• products involved in immune function and the inflammatory
cascade
• cell signalling
• gene expression and cell cycle control

46. ninab@igennus.com
www.igennus.com
drninabailey.co.uk
01223 421434

47. RBC content of EPA (%)
The effect of EPA supplementation on red blood cell (RBC)
membranes EPA content
Maki & Rains, 2012
Time (weeks)

48. Fatty acid levels ( g/g)
Changes in erythrocyte membrane omega-3 fatty acid levels
following 12 weeks treatment with 1g ethyl-EPA
Base line
Boston et al., 2004
Week 12

49. References
•
•
•
•
•
•
•
•
•
•
•
Alfano, C. M., I. Imayama, et al. (2012). "Fatigue, inflammation, and omega-3 and omega-6 fatty acid intake among breast cancer
survivors." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30(12): 1280-1287.
Azrad, M., C. Turgeon, et al. (2013). "Current Evidence Linking Polyunsaturated Fatty Acids with Cancer Risk and Progression."
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Bernard-Gallon, D. J., C. Vissac-Sabatier, et al. (2002). "Differential effects of n-3 and n-6 polyunsaturated fatty acids on BRCA1 and
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•
•
•
•
•
•
•
•
•
•
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•
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•
•
•
•
•
•
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