Fatty acids and breast cancer

Dr Nina BaileyBSc MSc PhD ANutr

Prostate

Lung

Bowel

Other sites

Breast

Lung

Bowel

Other sites

11%

47%46%

31%

12%

25%

14%

14%

Common cancers (males vs females) UK, 2010

http://www.cancerresearchuk.org/cancer-info/cancerstats/incidence/commoncancers

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:

GenderHormonesAgingReproductive historyHRT/birth controlBreast density

Genetic risk factorsFamily historyAlcohol consumptionObesitySedentary lifestyleDietary factors

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

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

• Cell fluidity• Metabolism• Growth and development• Brain structure and function

• Eicosanoid production Immunity Cardiovascular health Inflammation

• Cell cycle control

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)

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 cancerAA/EPA ratio was 22.232+1.852 compared to 14.25+1.083 for healthy subjects (median age 70; range 53 - 81) Breast cancerThe AA/EPA ratio was 21.029+2.584 compared to 12.10+1.414 in healthy subjects (median age 77; range 44 - 86)

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

Resoleomics - the process of inflammation resolution In

flam

mat

ory

resp

onse

Initiation Resolution Termination

PGE2

LTB4

Eicosanoid switch Stop signal

Time

Pro-inflammatory reduced

Anti-inflammatory increased

Bosma-den Boer et al., 2013

Alfano et al., 2012

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

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

Phospholipid

Phospholipase A2

Arachidonic acid

PGH2

COX-1

PGD2 PGE2 PGF2 a PGI2

COX-2

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 expressedCOX-2 is inducible and expressed only in response to certain stimuli

COX-2 is over-expressed in cancer

Arachidonic acid

COX-1

Constitutive‘gate-keeping functions’

Homeostatic function

Gastrointestinal tract

Renal tract

Platelet function

Macrophage differentiation

COX-2

InducedInflammation

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

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

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

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

Arachidonic acid

COX-1

Constitutive‘gate-keeping functions’

Homeostatic function

Gastrointestinal tract

Renal tract

Platelet function

Macrophage differentiation

COX-2

InducedInflammation

Cancer

Block

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 non-steroidal 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

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

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 case-control 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

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

COX-2 COX-2 inhibitor

Aromatase Prostaglandin Angiogenesis

Oestrogen Facilitation of tumour growth

Oestrogen dependant growth

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)

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?

Arachidonic acid

COX-1

Constitutive‘gate-keeping functions’

Homeostatic function

Gastrointestinal tract

Renal tract

Platelet function

Macrophage differentiation

COX-2

InducedInflammation

Cancer

EPA

EPA

High arachidonic acid levels

Pro-inflammatory ‘cancer driving’ prostaglandins COX-2

Increased EPA lowers arachidonic acid levels

Anti-inflammatory ‘cancer-suppressing

prostaglandins COX-2

Increased EPA lowers arachidonic acid levels

Anti-inflammatory ‘cancer-suppressing

prostaglandins

EPA competes with AA for COX-2

The role of EPA as a competitive inhibitor

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

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

Welch et al., 2002

Cod 29.9%Tuna 16.4%Salmon 14.2%Haddock 13.0%Plaice 7.6%Herring 6.0%Mackerel 3.0%

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

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

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)

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

• 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

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

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

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

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

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

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)

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)

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-a, IL-b1

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

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

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

ninab@igennus.comwww.igennus.comdrninabailey.co.uk

01223 421434

The effect of EPA supplementation on red blood cell (RBC) membranes EPA content

Time (weeks)

RBC

cont

ent o

f EPA

(%)

Maki & Rains, 2012

Base line Week 12

Changes in erythrocyte membrane omega-3 fatty acid levels following 12 weeks treatment with 1g ethyl-EPA

Fatt

y a

cid

levels

(m

g/g

)

Boston et al., 2004

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of data from 21 independent prospective cohort studies." BMJ 346: f3706.• Ziegler, R. G., R. N. Hoover, et al. (1993). "Migration patterns and breast cancer risk in Asian-American women." Journal of the

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