Linoleic Acid and Cancer

I believe preliminary evidence is coming out that shows linoleic acid is a promoter of certain cancers. Let’s examine the evidence supporting this claim, beginning with studies done on animals.

Evidence From Animal Studies

In the first study we’ll look at rats were fed diets with variable levels of linoleic acid and given the carcinogen dimethylbenz(a)anthracene. The authors stated “Mammary tumorigenesis was very sensitive to linoleate intake”, with more linoleic acid in the diet increasing tumor formation.

In another study, rats were fed corn oil, coconut oil, and a fish oil and exposed to a carcinogen that induces mammary tumors. The fish oil and coconut oil resulted in the same amount of mammary tumors, while the corn oil produced significantly more tumors. The authors stated “The protective effect of menhaden oil and coconut oil may be due, at least in part, to the decreased linoleic acid content of these diets relative to the corn oil diet”.

In a study in which rats injected with the carcinogen azoxymethane, rats fed corn oil and safflower oil (high in linoleic acid) had increased numbers of colon tumors, while rats fed coconut oil, olive oil, and MCT oil (low in linoleic acid) did not.

In a study in which rats were fed sunflower, rapeseed, olive, and coconut oil, the authors wrote “Our results indicate that a high linoleic acid diet may contribute to oxidative stress in the liver of female rats leading to a marginal increase in oxidative DNA-damage”.

In perhaps my favorite of these studies, rats were fed corn, olive, coconut, and safflower and cancer was initiated using N-nitrosomethylurea. There was a direct correlation between the linoleic acid content of the diet and mammary tumor incidence. The study’s authors suggest linoleic acid increases tumor incidence via its role as a prostaglandin precursor.

Epidemiological Evidence

Of course, these prior studies were all performed with rats given a carcinogen. The practical application of these studies is unsurprisingly a bit limited. Let’s examine the epidemiological evidence.

In an ecologic study examining the correlation between fats of fish, animal, and vegetable origin and breast cancer mortality from 1961 to 1986 in 30 countries, vegetable fat was found to be positively correlated with breast cancer mortality rates.

In a population based cohort study, 61,471 women in Sweden were examined and dietary patterns were obtained via food questionnaire. At the 4.2 year mark of this study, a significant positive association was found between polyunsaturated fat intake and breast cancer incidence. The majority of the polyunsaturated fat consumed came from linoleic acid.

In China, an ecologic correlation analysis was performed to explain the rapid increase in colon cancer. Analysis revealed “statistically significant positive associations…between colon cancer rates and per capita consumption of vegetable oil”.

Israel, which has some of the highest dietary intakes of linoleic acid, has high levels of cancer compared to western nations, especially in women. I suspect this is due to linoleic acid being especially promoting of breast cancer.

In this prospective study, 11,699 women were surveyed. Ultimately, a linoleic acid rich dietary pattern was associated with an increased risk of breast cancer.

Finally, in an epidemiological study on the role of dietary fat and cancer, polyunsaturated fat (specifically linoleic acid) was associated with increased incidence of breast and prostate cancers.

What About Controlled Trials?

Epidemiological studies are prone to confounding variables, making it difficult to cite such studies as definitive proof of the role linoleic acid’s role in promoting cancer. In a large controlled clinical trial involving 846 men in which vegetables oils (rich in linoleic acid) were substituted for saturated fats in the diet, cancer deaths increased notably in the vegetable oil group. Worth noting is the time required before this trend was noticable: cancer deaths didn’t begin increasing until about 2 years into the study, as can be seen in this diagram:

A similar study had different findings; in trial in which men either replaced fats in their diet with soybean oil (a linoleic acid rich oil) or continued eating their same diet. Out of about 200 people in each group, 2 developed cancer in the soybean oil group and 8 developed cancer in the control group.

In the Lyons Diet Heart Study, 605 men and women were divided into 2 groups, one experimental and one control. The experimental group received dietary advice and were given olive oil and canola oil to replace fats in the diet. Compared to the control group, the experimental group consumed 32% less linoleic acid. After 4 years there had been 17 cases of cancer in the control group and only 7 in the experimental group. Among members of the experimental group, intake of linoleic acid was higher in those who developed cancer. However, the experimental group also ate more fruits and vegetables, among other potentially beneficial foods, so it’s difficult to tease out proof of linoleic acid’s status as a cancer promoter, but this study is interesting nonetheless.

In the Oslo Diet-Heart Study, 206 men were allocated into 2 groups. The experimental group was told to increase vegetable oil (rich in linoleic acid) in the diet (among other dietary changes) while the other group was told to continue their diet as normal. After 11 years, their were 7 cases of cancer in the vegetable oil group and 5 in the control group. Unlike in the Lyons study, it was the group eating more linoleic acid that received more fruits and vegetables (and other foods), yet still more cancer occurred. Again, multiple dietary variables confound the results of this study, but this study also does not refute my hypothesis.

Finally, the Minnesota Coronary Survey Study utilized more than 8,000 institutionalized men and women and manipulated the fatty acid composition of their diets. The control diet contained roughly 5% of calories as polyunsaturated fat, mostly from linoleic acid. The treatment diet contained 15% of calories as polyunsaturated fat, mostly from linoleic acid. This study was a bit short (with a mean duration of a year) but at 20 terminal neoplasms in the control group and 23 in the experimental group, the higher linoleic acid diet resulted in 15% more deaths from cancer. So it was a small difference in favor of the low linoleic acid group. Unfortunately I was unable to find the rate of non fatal cancers which may have further illuminated a potential disparity between the two groups.

Conclusion

The relationship between diet and cancer is a highly complicated one, but I think one important component that deserves attention and increased study is the connection between linoleic acid intake and the development of cancer.

Edit: I decided to make an addendum to this post by adding a section where I speculate how linoleic acid causes cancer. Essential, I delve into the biology and pretend like I know what I’m talking about…

How Does Linoleic Acid Cause Cancer?

Honestly, we have a long way to go before this question is answered. We still need more evidence to prove linoleic acid even causes cancer. However, speculation is always fun, so let’s do that. Warning: serious nerd speak is coming up.

Linoleic acid is a substrate for arachidonic acid. Arachidonic acid is converted into prostaglandins by the cyclooxygenase enzymes COX 1 & 2. Several studies have found that NSAID’s, which block both the cyclooxygenases, reduce the risk of certain cancers (10,12,13,14,15,16) though the effect is often small (36). PGE2, one of these prostaglandins, is also found in higher concentrations in tumors than other cells (18) and has been linked to cancer development (17), at least in part because it may increase tumor angiogenesis (45,46) although PGE2 is also likely not the only factor (35). Another speculation is that prostaglandins may increase cancer by inhibiting apoptosis (19,20,47,48), a biological process that helps prevents cancer development.

Similarly, 5-lipooxygenase is an enzyme that converts arachidonic acid to several leukotrienes. There is preliminary evidence that this 5-lipooxygenase pathway plays a role in the occurrence and progression of various cancers (24,25,26,27,28,29,30,31,32,33) and that blocking this enzyme decreases cancer development (21,22,23). 5-lipooxygenase-activating protein (or FLAP) is necessary for the activation of 5-lipooxygenase. In an interesting study, women with variations of the gene coding for FLAP had higher rates of breast cancer when intake of linoleic acid was above 17.4 grams a day (34).

However I don’t think the above mechanisms are the full picture to this story. Inhibiting the cyclooxygenases and 5-lipooxygenase don’t seem to entirely remove the effect of linoleic acid on cancer. I think lipid peroxidation plays a big role in the carcinogenic nature of linoleic acid (9). Lipid peroxidation is essentially the process by which a free radical oxidizes a fatty acid and polyunsaturated fats like linoleic acid are very susceptible to this process. Lipid peroxidation results in the formation of compounds (especially malondialdehyde, or MDA) which are mutagenic and carcinogenic. Evidence is also coming out that these compounds form what are known as DNA adducts, which is the process by which a piece of DNA is covalently bonded to a cancer causing chemical (41). The following diagram represents a suggested mechanism by which this occurs:

MDA adducts have been found to accumulate in breast tissue and may play a role in the etiology of breast cancer (42). These adducts are increased by consumption of linoleic acid and are especially prevalent in women (43) and are increasingly being recognized as playing a role in the development of prostate, colon, and breast cancer (and perhaps others) (43). The reason women seem especially prone to development of these adducts may be due to interactions with estrogen. This role has yet to be fully explained, but some speculation have been made based on current evidence (44), seen in this diagram:

There is evidence that linoleic acid has numerous effects which may be increase cancer, many of which I just didn’t have time to get into. This diagram demonstrates just some of the possible mechanisms:

The point is, it’s very complicated. I hope to study this more in the future.

References:

9. http://www.ncbi.nlm.nih.gov/pubmed/22234166
10. http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1098-2744(199908)25:4%3C231::AID-MC1%3E3.0.CO;2-F/abstract
11. http://jn.nutrition.org/content/131/4/1125.abstract?ijkey=8ba8a50f5dbc2cc511435238d83ef7294b0061ec&keytype2=tf_ipsecsha
12. http://www.ncbi.nlm.nih.gov/pubmed/15998950
13. http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1098-2744(199908)25:4%3C231::AID-MC1%3E3.0.CO;2-F/abstract
14. http://www.ncbi.nlm.nih.gov/pubmed/15668504
15. http://www.ncbi.nlm.nih.gov/pubmed/15734963
16. http://www.ncbi.nlm.nih.gov/pubmed/8385741
17. http://www.sciencedirect.com/science/article/pii/S0163725899000261
18. http://cancerres.aacrjournals.org/content/60/17/4705.abstract?ijkey=806f6da25bfdd7abbc8eaa4ba8c0193e0c6fcca2&keytype2=tf_ipsecsha
19. http://www.ncbi.nlm.nih.gov/pubmed/11837738?dopt=Abstract
20. http://cancerres.aacrjournals.org/content/62/3/625.abstract?ijkey=9ca36ec0945d64af47f175f47ce54b74c78d4b31&keytype2=tf_ipsecsha
21. http://www.ncbi.nlm.nih.gov/pubmed/16185917?dopt=Abstract
22. http://www.fasebj.org/content/15/11/2007.full?ijkey=cd41eb24fae879b90ed8f53de7c19e835f91f41e&keytype2=tf_ipsecsha
23. http://www.ncbi.nlm.nih.gov/pubmed/17105440?dopt=Abstract
24. http://www.ncbi.nlm.nih.gov/pubmed/8609238?dopt=Abstract
25. http://www.ncbi.nlm.nih.gov/pubmed/17072961?dopt=Abstract
26. http://carcin.oxfordjournals.org/content/26/4/827.abstract?ijkey=8c98704a22924f6549fa58e8e99cc12e4afab4ad&keytype2=tf_ipsecsha
27. http://www.sciencedirect.com/science/article/pii/S0006291X97967991
28. http://www.sciencedirect.com/science/article/pii/S0006291X05024988
29. http://www.ncbi.nlm.nih.gov/pubmed/17616938?dopt=Abstract
30. http://www.ncbi.nlm.nih.gov/pubmed/16903934?dopt=Abstract
31. http://www.sciencedirect.com/science/article/pii/S0006291X05016724
32. http://cancerres.aacrjournals.org/content/65/14/6011.abstract?ijkey=78a056023f60c2d4c85ade0709ce45dccc052d4c&keytype2=tf_ipsecsha
33. http://clincancerres.aacrjournals.org/content/10/19/6703.abstract?ijkey=3cc3e5363bd1a5ce0a33df5e7b81827e7ce06b05&keytype2=tf_ipsecsha
34. http://cebp.aacrjournals.org/content/17/10/2748.long
35. http://www.ncbi.nlm.nih.gov/pubmed/9589432
36. http://www.ncbi.nlm.nih.gov/pubmed/15888492
37. http://www.ncbi.nlm.nih.gov/pubmed/16317153
38. http://www.ncbi.nlm.nih.gov/pubmed/8960090
39. http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&list_uids=10064852&cmd=Retrieve&indexed=google
40. http://www.ncbi.nlm.nih.gov/pubmed/15499577
41. http://carcin.oxfordjournals.org/content/17/10/2105.full.pdf
42. http://www.ncbi.nlm.nih.gov/pubmed/8877062
43. http://www.ncbi.nlm.nih.gov/pubmed/9264272
44. http://www.ncbi.nlm.nih.gov/pubmed/9472688
45. http://www.ncbi.nlm.nih.gov/pubmed/10536186?dopt=Abstract
46. http://www.gastrojournal.org/article/S0016-5085(01)96357-7/abstract?referrer=http://www.ajcn.org/content/79/6/935.full
47. http://cancerres.aacrjournals.org/content/62/9/2721.abstract?ijkey=0dbd6a5c1910fa26c9086d4c48221cf97df1c427&keytype2=tf_ipsecsha
48. http://onlinelibrary.wiley.com/doi/10.1002/ijc.1527/abstract?systemMessage=Wiley+Online+Library+will+be+disrupted+on+9+June+from+10%3A00-12%3A00+BST+%2805%3A00-07%3A00+EDT%29+for+essential+maintenance

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7 thoughts on “Linoleic Acid and Cancer

  1. Ossie Sharon, M.S., R.D. June 16, 2015 / 6:57 pm

    How does one request permissions for reuse of your original figures in a future publication?

    • Morgan June 16, 2015 / 7:28 pm

      It may depend on the copyright policy of the Journal in which the figures were published. Some do not have copyrights and can be freely used if properly cited, others may require you to contact the authors or journal for permission.

      • Ossie Sharon, M.S., R.D. June 16, 2015 / 9:10 pm

        Yes, but a couple of your figures do not note the source. I looked through your references, and none of them have the two figures flanking the following paragraph:

        “MDA adducts have been found to accumulate in breast tissue and may play a role in the etiology of breast cancer (42). These adducts are increased by consumption of linoleic acid and are especially prevalent in women (43) and are increasingly being recognized as playing a role in the development of prostate, colon, and breast cancer (and perhaps others) (43). The reason women seem especially prone to development of these adducts may be due to interactions with estrogen. This role has yet to be fully explained, but some speculation have been made based on current evidence (44), seen in this diagram:”

        Can you help?

        Thanks again.

    • Morgan June 16, 2015 / 11:17 pm

      Yes, it does appear I can’t immediately find those diagrams. Alas I wrote this post 3 years ago as a undergraduate when my blogging was fairly sloppy. Let me see if I can help you anyway. You can find a diagram somewhat similar to the one preceding the paragraph you posted here:

      http://carcin.oxfordjournals.org/content/17/10/2105.full.pdf

      The figure listed as “Scheme 3” in the above paper is essentially the same as my figure, albeit less visually appealing from a subjective viewpoint.

      As for the diagram following that paragraph, follow this link:

      http://onlinelibrary.wiley.com/store/10.1002/ijc.27479/asset/27479_ftp.pdf?v=1&t=ib0ck7lq&s=59cea33542b6419dbc4fb8637491df4321672663

      Figure 1 of this study basically covers the same hypothetical mechanism of estradiol redox signaling and it’s interaction with n-6 PUFA to produce LOP-adducts.

      Can I ask for what purpose you are looking for these figures?

      • Ossie Sharon, M.S., R.D. June 17, 2015 / 1:33 am

        Thank you very, very much. A university professor for whom I work was asked to contributed a chapter on “the role of diet in breast cancer prevention” to a multi-peer professional text “Trends in Breast Cancer Prevention” to be published by Springer in the near future. She saw this article and found these two images to provide excellent visuals to accompany the message of how excessive n-6 PUFA intake may drive breast cancer risk.
        Thanks again.

    • Morgan June 17, 2015 / 11:01 am

      I’m glad I could help. I would like to read this publication. If you wouldn’t mind letting me know when it is ultimately published I’d definitely appreciate it.

      • Ossie Sharon, M.S., R.D. June 17, 2015 / 11:40 am

        Will do! Thanks again.

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