Dairy products and breast cancer – what are the current evidences?

My favourite hot chocolate milk with rum !

I was intrigued by the late Professor Jane Plant’s inspiring story on how she beat cancer by giving up dairy products.  Her story and her books can be found in various websites. When Daily Telegraph published her story in 2014, the article triggered numerous complaints and she was being accused of misleading women by falsely suggesting a link between breast cancer and dairy products. Mind you, we are talking about the multi-million farming business here!

(http://www.telegraph.co.uk/foodanddrink/healthyeating/10868428/Give-up-dairy-products-to-beat-cancer.html).

Well, in my opinion, she was just sharing what she has experienced and how giving up dairy products improved the prognosis of her breast cancer. Similarly, in my case, having to live with benign breast disease with multiple cysts for a couple of years and how a simple dietary change within a short period of time gave me a diagnosis of breast cancer! I guess we missed out something there. 

Deliciously crazy french onion soup with lots of cheese!

A large number of studies have investigated the relation between dairy food consumption and breast cancer risk, unfortunately with conflicting results. Some studies were well-designed but some have obvious flaws. Most cancer-related organizations prefer to take the middle path by saying there were no significant relationship between dairy products intake and cancer.

Nevertheless, there are studies that positively link dairy products intake and risk of cancer worthy of attention!

• In an ecologic study from 1916-1975 where data obtained from the Norwegian Cancer Registry were analysed to compare risk of breast cancer among women who went through the period before, during, or after World War II, breast cancer risk in 1975 was found to be 2.7-times higher than in 1916. This risk has been associated with changes of life style factors after World War II including milk intake (Tretli and Gaard 1996).

• In another prospective study to examine the relationship between energy and fat consumption and the risk of breast cancer among 25,892 Norwegian women, women consuming 0.75 L or more of full-fat milk daily had a relative risk of 2.91 compared with those who consumed 0.15 L or less (Gaard et al. 1995).

• Data from the Nurses' Health Study II found that women who ate red meat and two or more servings of high-fat dairy products (whole milk or butter) every day had a higher risk of breast cancer before menopause (Cho et al. 2003).

• A study and a mean follow up of 11.8 years on 1893 women diagnosed with early-stage invasive breast cancer from 1997 to 2000 concluded that intake of high-fat dairy was related to a higher risk of mortality after breast cancer diagnosis (Kroenke et al. 2013).

• In another recent large Swedish cohort study among people with lactose intolerance, it was demonstrated that people with lactose intolerance and low consumption of milk and other dairy products had a decreased risk of breast, lung, and ovarian cancers (Ji et al. 2015).  

• An increased ovarian cancer risk was observed for whole milk consumption and lactose intake among African-American women in a population-based case-control study (Qin et al. 2016).

• A study to assess differences in dietary intakes in breast cancer survivors and women without a history of breast cancer revealed that survivors tend to consume less dairy products, animal protein, total protein, and calcium, but more legumes, non-citrus fruit, and carbohydrates (Lay et al. 2016).

• Experiments carried out in the laboratory indicated that consumption of commercial whole and non-fat milk for 20 weeks doubled the incidence chemical-induced mammary tumors in rats  (Qin et al. 2007).  

Cheese, glorious cheese......

A variety of mechanisms suggesting ways dairy products influence breast cancer risk was hypothesized.  For example, the presence of components such as calcium, vitamin D, insulin-like growth factors (Ma et al. 2001, Qin et al. 2009), conjugated linoleic acid (Voorrips et al. 2002), and estrogenic hormones (Brinkman et al. 2010) are thought to be contributing to the risks.  

• The Melbourne Collaborative Cohort Study, which included women from Australia, New Zealand, the United Kingdom, Italy, and Greece, found that dairy intake was statistically significantly related to higher levels of estradiol and free estradiol (Brinkman et al. 2010).

• Since estrogens are considered the major etiologic pathway to breast cancer, the influence of dairy intake on estrogens should be strongly considered in understanding how dairy  would affect breast cancer–specific outcome (Kroenke et al. 2013).

Recently, more defined molecular mechanisms were proposed. To appreciate the mechanisms behind milk-induced cell proliferation and growth, we need to understand briefly the role of FTO gene, the microRNAs (miRNAs) found in cow’s milk and the mTORC1 signalling pathways.

• FTO (fat mass- and obesity-associated) gene is widely expressed in a variety of human tissues and is detected in the brain, pancreatic islets, and the liver (Frayling et al. 2007, Bodo C. Melnik 2015). The FTO gene has been recognized to play a crucial role in the early-life determination of body weight, body composition and energy balance (Sebert et al. 2014).

• FTO plays a predominant role in DNA demethylation and m6A-dependent mRNA demethylation (Frayling et al. 2007, Gerken et al. 2007, Jia et al. 2011).  FTO-mediated demethylation of mRNAs increases transcriptional activity and generates mRNA splice variants that are critically involved in adipogenesis  (Zhao et al. 2014), appetite control (Jia et al. 2011), and mTORC1 activation (Gulati et al. 2013, Han et al. 2012). It is important to note that mTORC1 activation eventually leads to cell growth and proliferation and is known to be a marker in breast cancer.

• In addition, FTO promotes transcription and increases genomic transcriptional activity, a requirement for postnatal growth and lactation coordination.   

• FTO also plays a critical role in milk production. The mRNA of prolactin, the most important hormone promoting lactation, is regulated via m6A methylation which was dependent on FTO activity (Bian et al. 2015, Carroll et al. 1990).

Enhancing both milk quality and quantity is a major selection criterion for the genetic improvement of livestock. High performance dairy cows with higher milk yield have an enhanced expression of miRNA-29 (Bian et al. 2015). MiRNAs are non-coding RNA molecules that regulates gene expression.

• Abundance of miRNA-29s increases both bovine FTO mRNA and protein levels of these cells (via inhibition of methylation).  

• DNA methylation is a process which methyl groups are added to DNA, and if the methyl groups are located at the genes, then the genes will not be transcribed or translated into proteins. On the other hand, demethylation is a process that removes the methyl group from the DNA.

• Bovine miRNA-29s, which are identical with human miRNA-29s, and bovine FTO mRNA, which is highly homologous (similar) to human FTO mRNA, are taken up by humans via the uptake of milk exosomes by human macrophages ( a type of immune cell) (Bian et al. 2015).

• In milk, miRNAs are encapsulated in exosomes which are highly resistant against harsh degrading conditions and thus, facilitating uptake by endocytosis. MiRNAs of commercial cow´s milk are known to survive processing such as pasteurization, homogenization and refrigeration (Howard et al. 2015).  

• MiRNAs are known to be absorbed from cow milk and affect gene expression in peripheral blood mononuclear cells of human subjects (Baier et al. 2014). Since, the majority of bovine miRNAs have nucleotide sequences complementary to human gene transcripts; the absorbed miRNAs are likely to regulate human genes (Baier et al. 2014).

   

In short:

• Milk stimulates the expression of FTO, which functions as a critical amplifier of the transcriptional machinery for postnatal growth.

• Milk activates the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), which induces mTORC1-dependent translation, a crucial requirement for cell growth and proliferation (B. C. Melnik 2015).

• mTORC1 activation eventually leads to increased growth and proliferation and is known to be a marker in certain cancers.

• Milk proteins are a rich nutrient source of branched-chain essential amino acids (BCAAs) and glutamine which also play an important role in FTO expression and mTORC1 activation (Lenders et al. 2009, Millward et al. 2008).  

• In comparison to human breast milk, equivalent volumes of cow´s milk transfer three times more BCAAs to the human and thus may overstimulate BCAA-driven FTO and mTORC1 activation, both of which triggers cell growth (B. C. Melnik 2015).  

In my humble opinion, if you have benign breast diseases, you may want to seriously considering limiting dairy products from your diet. I wished I knew this earlier, but I am definitely not crying over spilled milk!

 

Blissful ice cream......sigh...

References:

Baier SR, Nguyen C, Xie F, Wood JR and Zempleni J (2014). MicroRNAs are absorbed in biologically meaningful amounts from nutritionally relevant doses of cow milk and affect gene expression in peripheral blood mononuclear cells, HEK-293 kidney cell cultures, and mouse livers. J Nutr, 144(10), 1495-1500.

Bian Y, Lei Y, Wang C, Wang J, Wang L, Liu L, et al. (2015). Epigenetic Regulation of miR-29s Affects the Lactation Activity of Dairy Cow Mammary Epithelial Cells. J Cell Physiol, 230(9), 2152-2163.

Brinkman MT, Baglietto L, Krishnan K, English DR, Severi G, Morris HA, et al. (2010). Consumption of animal products, their nutrient components and postmenopausal circulating steroid hormone concentrations. European journal of clinical nutrition, 64(2), 176-183.

Carroll SM, Narayan P and Rottman FM (1990). N6-methyladenosine residues in an intron-specific region of prolactin pre-mRNA. Molecular and cellular biology, 10(9), 4456-4465.

Cho E, Spiegelman D, Hunter DJ, Chen WY, Stampfer MJ, Colditz GA, et al. (2003). Premenopausal fat intake and risk of breast cancer. Journal of the National Cancer Institute, 95(14), 1079-1085.

Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. (2007). A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science (New York, N.Y.), 316(5826), 889-894.

Gaard M, Tretli S and Loken EB (1995). Dietary fat and the risk of breast cancer: a prospective study of 25,892 Norwegian women. Int J Cancer, 63(1), 13-17.

Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, et al. (2007). The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science (New York, N.Y.), 318(5855), 1469-1472.

Gulati P, Cheung MK, Antrobus R, Church CD, Harding HP, Tung YC, et al. (2013). Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proceedings of the National Academy of Sciences of the United States of America, 110(7), 2557-2562.

Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK, et al. (2012). Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell, 149(2), 410-424.

Howard KM, Jati Kusuma R, Baier SR, Friemel T, Markham L, Vanamala J, et al. (2015). Loss of miRNAs during processing and storage of cow's (Bos taurus) milk. Journal of agricultural and food chemistry, 63(2), 588-592.

Ji J, Sundquist J and Sundquist K (2015). Lactose intolerance and risk of lung, breast and ovarian cancers: aetiological clues from a population-based study in Sweden. British journal of cancer, 112(1), 149-152.

Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, et al. (2011). N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nature chemical biology, 7(12), 885-887.

Kroenke CH, Kwan ML, Sweeney C, Castillo A and Caan BJ (2013). High- and Low-Fat Dairy Intake, Recurrence, and Mortality After Breast Cancer Diagnosis. Journal of the National Cancer Institute, 105(9), 616-623.

Lay WA, Vickery CR, Ward-Ritacco CL, Johnson KB, Berg AC, Evans EM, et al. (2016). Comparison of Intake of Animal and Plant Foods and Related Nutrients in Postmenopausal Breast Cancer Survivors and Controls. Journal of nutrition in gerontology and geriatrics, 35(1), 15-31.

Lenders CM, Liu S, Wilmore DW, Sampson L, Dougherty LW, Spiegelman D, et al. (2009). Evaluation of a novel food composition database that includes glutamine and other amino acids derived from gene sequencing data. European journal of clinical nutrition, 63(12), 1433-1439.

Ma J, Giovannucci E, Pollak M, Chan JM, Gaziano JM, Willett W, et al. (2001). Milk intake, circulating levels of insulin-like growth factor-I, and risk of colorectal cancer in men. Journal of the National Cancer Institute, 93(17), 1330-1336.

Melnik BC (2015). Milk--A Nutrient System of Mammalian Evolution Promoting mTORC1-Dependent Translation. International journal of molecular sciences, 16(8), 17048-17087.

Melnik BC (2015). Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases. Journal of Translational Medicine, 13, 385.

Millward DJ, Layman DK, Tome D and Schaafsma G (2008). Protein quality assessment: impact of expanding understanding of protein and amino acid needs for optimal health. Am J Clin Nutr, 87(5), 1576s-1581s.

Qin B, Moorman PG, Alberg AJ, Barnholtz-Sloan JS, Bondy M, Cote ML, et al. (2016). Dairy, calcium, vitamin D and ovarian cancer risk in African-American women. British journal of cancer, 115(9), 1122-1130.

Qin LQ, He K and Xu JY (2009). Milk consumption and circulating insulin-like growth factor-I level: a systematic literature review. International journal of food sciences and nutrition, 60 Suppl 7, 330-340.

Qin LQ, Xu JY, Tezuka H, Li J, Arita J, Hoshi K, et al. (2007). Consumption of commercial whole and non-fat milk increases the incidence of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats. Cancer detection and prevention, 31(4), 339-343.

Sebert S, Salonurmi T, Keinanen-Kiukaanniemi S, Savolainen M, Herzig KH, Symonds ME, et al. (2014). Programming effects of FTO in the development of obesity. Acta physiologica (Oxford, England), 210(1), 58-69.

Tretli S and Gaard M (1996). Lifestyle changes during adolescence and risk of breast cancer: an ecologic study of the effect of World War II in Norway. Cancer causes & control : CCC, 7(5), 507-512.

Voorrips LE, Brants HA, Kardinaal AF, Hiddink GJ, van den Brandt PA and Goldbohm RA (2002). Intake of conjugated linoleic acid, fat, and other fatty acids in relation to postmenopausal breast cancer: the Netherlands Cohort Study on Diet and Cancer. Am J Clin Nutr, 76(4), 873-882.

Zhao X, Yang Y, Sun BF, Shi Y, Yang X, Xiao W, et al. (2014). FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell research, 24(12), 1403-1419.