Maternal PUFA Intake Increases Breast Cancer Risk in Female Offspring

Also see:
Hormonal profiles in women with breast cancer
PUFA Promote Cancer
PUFA Inhibit Glucuronidation
PUFA Increases Estrogen
PUFA, Estrogen, Obesity and Early Onset of Puberty
Prenatal Exposure to Radiation Increases Cancer Risk
Maternal Ingestion of Tryptophan and Cancer Risk in Female Offspring
Israeli Paradox: High Omega -6 Diet Promotes Disease

Elevated gestational estrogen and a maternal diet high in polyunsaturates contribute to increased cancer risk in the offspring.

Nutrition. 1999 May;15(5):392-401.
The influence of maternal diet on breast cancer risk among female offspring.
Hilakivi-Clarke L, Clarke R, Lippman M.
The induction of breast cancer is a long process, containing a series of biological events that drive a normal mammary cell towards malignant growth. However, it is not known when the initiation of breast cancer occurs. One hypothesis is that a high estrogenic environment during the perinatal period increases subsequent breast cancer risk. There are many sources of extragonadal estrogens, particularly in the diet. The purpose of this paper is to review the evidence that a high maternal intake of dietary fats increases serum estrogens during pregnancy and increases breast cancer risk in daughters. Our animal studies show that a high maternal consumption of corn oil consisting mainly of linoleic acid (omega-6 polyunsaturated fatty acid, PUFA), increases both circulating estradiol (E2) levels during pregnancy and the risk of developing carcinogen-induced mammary tumors among the female rat offspring. A similar increase in breast cancer risk occurs in female offspring exposed to injections of E2 through their pregnant mother. Our data suggest that the mechanisms by which an early exposure to dietary fat and/or estrogens increases breast cancer risk is related to reduced differentiation of the mammary epithelial tree and increased number of mammary epithelial cell structures that are known to the sites of neoplastic transformation. These findings may reflect our data of the reduced estrogen receptor protein levels and protein kinase C activity in the developing mammary glands of female rats exposed to a high-fat diet in utero. In summary, a high dietary linoleic acid intake can elevate pregnancy estrogen levels and this, possibly by altering mammary gland morphology and expression of fat- and/or estrogen-regulated genes, can increase breast cancer risk in the offspring. If true for women, breast cancer prevention in daughters may include modulating the mother’s pregnancy intake of some dietary fats.

Mol Cell Biochem. 1998 Nov;188(1-2):5-12.
Timing of dietary fat exposure and mammary tumorigenesis: role of estrogen receptor and protein kinase C activity.
Hilakivi-Clarke L, Clarke R.
The possible association between a high fat diet and increased breast cancer risk has remained controversial. This largely reflects the conflicting data obtained from migrant, case control and animal studies, which generally support this association, and cohort studies which often fail to show a link between fat and breast cancer. The mammary gland is particularly sensitive to estrogens during fetal development, leading us to hypothesize that dietary fat levels during this period may significantly influence breast cancer risk. Using chemically-induced mammary tumors in rats as our experimental model, we have demonstrated the ability of a maternal diet, high in the polyunsaturated fatty acid (PUFA) linoleic acid, to alter mammary gland differentiation, accelerate the onset of sexual maturation, and increase breast cancer risk. The mammary glands of female rats exposed to a high-fat diet in utero have more of the undifferentiated structures (terminal end buds) and fewer of the differentiated structures (alveolar buds) than the glands of rats exposed to a low-fat diet in utero. Furthermore, these mammary glands contain lower levels of total estrogen receptors and have reduced total protein kinase C activity. These effects appear to be mediated by an increase in the serum estradiol levels of pregnancy, which are elevated at least 30% in pregnant dams fed a high-fat diet. Furthermore, the administration of estradiol to pregnant dams produces effects on mammary gland development, onset of puberty and sensitivity to chemical carcinogenesis comparable to those seen in the offspring of rats fed a high fat diet during pregnancy. Our results, thus, support the hypothesis based on epidemiological data that high maternal estrogen levels increase daughters’ breast cancer risk. The results also suggest that a high-fat diet may be an important factor in increasing pregnancy estrogenic activity.

[propaganda study: omega -3 compared to omega -6 PUFA. 38% still developed cancer on the omega -3 enriched diet.]
Clin Cancer Res. 2002 Nov;8(11):3601-10.
Dietary modulation of pregnancy estrogen levels and breast cancer risk among female rat offspring.
Hilakivi-Clarke L, Cho E, Cabanes A, DeAssis S, Olivo S, Helferich W, Lippman ME, Clarke R.
Against the hypothesis that high estrogen levels in utero increase the risk of developing breast cancer in later life are data showing that pregnancy estrogen levels are significantly higher in Asian women who have low breast cancer risk than in Caucasian women. We investigated whether maternal dietary intake of genistein or n-3 polyunsaturated fatty acids (PUFAs), which are typical to Asian but not Caucasian diet, affect pregnancy estrogen levels and susceptibility to mammary tumorigenesis among offspring.
For that purpose, pregnant female Sprague Dawley rats were fed isocaloric AIN-93-based diets containing either at 15 mg (low), 150 mg (medium), or 300 mg (high)/kg genistein/diet or low- or high-fat (16 versus 39% energy from fat) diet composed either of n-3 PUFA menhaden oil or n-6 PUFA corn oil. All diets were switched to regular AIN-93 diet when pups were born.
Maternal intake of n-3 PUFA diets significantly increased pregnancy 17 beta-estradiol (E2) levels (48% increase when compared with high n-6 PUFA diet; P < 0.0045). High genistein exposure also increased pregnancy estrogen levels, but the increase did not reach statistical significance (P < 0.14). The offspring of high-fat n-3 PUFA-consuming dams were significantly less likely to develop 7,12-dimethylbenz-[a]anthracene-induced mammary tumors (38% of these rats developed tumors during week 17 versus 64% of high n-6 PUFA offspring; P < 0.003). Maternal genistein intake did not affect offspring’s tumor incidence. The mammary glands of high fat n-3 PUFA offspring contained more lobules (P < 0.07) and were thus more differentiated, whereas the glands of high genistein offspring contained more terminal end buds (P < 0.0015), which are the sites of malignant transformation.
Our findings indicate that the elevated estrogen levels in the n-3 PUFA mothers were linked to reduced rather than increased breast cancer risk among their offspring, suggesting that other effects of n-3 PUFA may counteract the effects of high fetal estrogenicity on the mammary gland. High maternal genistein intake did not reduce offspring’s breast cancer risk, and therefore high maternal soy intake in Asian women may not be associated with daughters’ low breast cancer risk.

Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9372-7.
A maternal diet high in n – 6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring.
Hilakivi-Clarke L, Clarke R, Onojafe I, Raygada M, Cho E, Lippman M.
We hypothesized that feeding pregnant rats with a high-fat diet would increase both circulating 17beta-estradiol (E2) levels in the dams and the risk of developing carcinogen-induced mammary tumors among their female offspring. Pregnant rats were fed isocaloric diets containing 12% or 16% (low fat) or 43% or 46% (high fat) of calories from corn oil, which primarily contains the n – 6 polyunsaturated fatty acid (PUFA) linoleic acid, throughout pregnancy. The plasma concentrations of E2 were significantly higher in pregnant females fed a high n – 6 PUFA diet. The female offspring of these rats were fed with a laboratory chow from birth onward, and when exposed to 7,12-dimethylbenz(a)anthracene had a significantly higher mammary tumor incidence (60% vs. 30%) and shorter latency for tumor appearance (11.4 +/- 0.5 weeks vs. 14.2 +/- 0.6 weeks) than the offspring of the low-fat mothers. The high-fat offspring also had puberty onset at a younger age, and their mammary glands contained significantly higher numbers of the epithelial structures that are the targets for malignant transformation. Comparable changes in puberty onset, mammary gland morphology, and tumor incidence were observed in the offspring of rats treated daily with 20 ng of E2 during pregnancy. These data, if extrapolated to humans, may explain the link among diet, early puberty onset, mammary parenchymal patterns, and breast cancer risk, and indicate that an in utero exposure to a diet high in n – 6 PUFA and/or estrogenic stimuli may be critical for affecting breast cancer risk.

J Natl Cancer Inst. 1996 Dec 18;88(24):1821-7.
Breast cancer risk in rats fed a diet high in n-6 polyunsaturated fatty acids during pregnancy.
Hilakivi-Clarke L, Onojafe I, Raygada M, Cho E, Clarke R, Lippman ME.
Women who took the synthetic estrogen diethylstilbestrol during pregnancy exhibit an elevated risk of breast cancer, whereas those who suffered from preeclampsia, which is associated with low circulating pregnancy estrogens, exhibit a reduced risk. Since a high-fat diet may increase circulating estrogen levels and possibly breast cancer risk, dietary factors during pregnancy could influence the risk of developing this disease.
We tested the hypothesis that consumption of a high-fat diet during pregnancy increases carcinogen-induced mammary tumor incidence in rats.
Pregnant or virgin female Sprague-Dawley rats that had been previously treated with 10 mg 7, 12-dimethylbenz[a]anthracene (DMBA) by oral gavage when 55 days old were assigned to one of two isocaloric diets containing either 16% calories from fat (low-fat) or 43% calories from fat (high-fat) for the length of pregnancy or for the equivalent time of approximately 21 days. There were 20 pregnant and 10 nonpregnant DMBA-treated rats per group. Ten additional pregnant animals (not previously treated with DMBA) per group were used for hormone analysis. The fat source used was corn oil, which is high in n-6 polyunsaturated fatty acids, primarily linoleic acid. The animals were checked for tumors at least once per week by palpation. The tumor size, number, and latency to appearance after carcinogen exposure were recorded. The statistical significance of observed differences was tested by use of appropriate two-sided tests.
Female rats on different diets had virtually identical food intakes and weight gains during pregnancy. On gestation day 19, serum estradiol levels were approximately twofold higher in rats fed a high-fat diet than in rats fed a low-fat diet (P < .02). The serum insulin levels and insulin/glucose ratios (an index of insulin resistance) in rats fed the high-fat diet were approximately twofold lower than in rats fed the low-fat diet, but the differences did not reach statistical significance (P < .09 and P < .09, respectively). On week 18 following DMBA administration, the number of rats developing mammary tumors was significantly higher in the group exposed to a high-fat diet (40% of animals) than in the group exposed to a low-fat diet (10% of animals) during pregnancy (P < .05). Tumor multiplicity, latency to tumor appearance, and size of tumors upon first detection were similar among the dietary groups. No intergroup differences in the mammary tumor incidence were noted in virgin animals that were exposed to the high- or low-fat diets for an equivalent period of time.
Our findings indicate that consumption of a diet high in fat (primarily in the form of n-6 polyunsaturated fatty acids) during pregnancy increases the risk of developing carcinogen-induced mammary tumors, possibly by increasing the pregnancy levels of circulating estrogens.
If further studies find that the results from animal model studies are applicable to humans, some human breast cancers may be preventable by dietary manipulations during pregnancy.

Oncol Rep. 1998 May-Jun;5(3):609-16.
Maternal genistein exposure mimics the effects of estrogen on mammary gland development in female mouse offspring.
Hilakivi-Clarke L, Cho E, Clarke R.
Human and animal data indicate that a high maternal estrogen exposure during pregnancy increases breast cancer risk among daughters. This may reflect an increase in the epithelial structures that are the sites for malignant transformation, i.e., terminal end buds (TEBs), and a reduction in epithelial differentiation in the mammary gland. Some phytoestrogens, such as genistein which is a major component in soy-based foods, and zearalenone, a mycotoxin found in agricultural products, have estrogenic effects on the reproductive system, breast and brain. The present study examined whether in utero exposure to genistein or zearalenone influences mammary gland development. Pregnant mice were injected daily with i) 20 ng estradiol (E2); ii) 20 microg genistein; iii) 2 microg zearalenone; iv) 2 microg tamoxifen (TAM), a partial estrogen receptor agonist; or v) oil-vehicle between days 15 and 20 of gestation. E2, genistein, zearalenone, and tamoxifen all increased the density of TEBs in the mammary glands. Genistein reduced, and zearalenone increased, epithelial differentiation. Zearalenone also increased epithelial density, when compared with the vehicle-controls. None of the treatments had permanent effects on circulating E2 levels. Maternal exposure to E2 accelerated body weight gain, physical maturation (eyelid opening), and puberty onset (vaginal opening) in the female offspring. Genistein and tamoxifen had similar effects on puberty onset than E2. Zearalenone caused persistent cornification of the estrus smears. These findings indicate that maternal exposure to physiological doses of genistein mimics the effects of E2 on the mammary gland and reproductive systems in the offspring. Thus, our results suggest that genistein acts as an estrogen in utero, and may increase the incidence of mammary tumors if given through a pregnant mother. The estrogenic effects of zearalenone on the mammary gland, in contrast, are probably counteracted by the permanent changes in estrus cycling.

Nat Commun. 2012 Sep 11;3:1053.
High-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring.
de Assis S, Warri A, Cruz MI, Laja O, Tian Y, Zhang B, Wang Y, Huang TH, Hilakivi-Clarke L.
“To test our hypothesis that maternal exposures during pregnancy to factors such as HF diet or a synthetic E2 lead to breast cancer in several generations, we fed pregnant Sprague–Dawley rats (F0) with either an AIN93G control diet or an isocaloric AIN93G-based high fat diet, containing 43% energy from corn oil, throughout gestation.”
“Maternal exposures to environmental factors during pregnancy influence the risk of many chronic adult-onset diseases in the offspring. Here we investigate whether feeding pregnant rats a high-fat (HF)- or ethinyl-oestradiol (EE2)-supplemented diet affects carcinogen-induced mammary cancer risk in daughters, granddaughters and great-granddaughters. We show that mammary tumourigenesis is higher in daughters and granddaughters of HF rat dams and in daughters and great-granddaughters of EE2 rat dams. Outcross experiments suggest that the increase in mammary cancer risk is transmitted to HF granddaughters equally through the female or male germ lines, but it is only transmitted to EE2 granddaughters through the female germ line. The effects of maternal EE2 exposure on offspring’s mammary cancer risk are associated with changes in the DNA methylation machinery and methylation patterns in mammary tissue of all three EE2 generations. We conclude that dietary and oestrogenic exposures in pregnancy increase breast cancer risk in multiple generations of offspring, possibly through epigenetic means.”

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