Effects of Milk and Milk Products Consumption on Cancer: A Review
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Effects of Milk and Milk Products Consumption on
Cancer: A Review
H. Davoodi, S. Esmaeili, and A.M. Mortazavian
Abstract: Milk is considered to be the only foodstuff that contains approximately all different substances known to be
essential for human nutrition. In terms of cancer risk, dairy foods have been reported as both protective and occasionally as
harmful. The evidence that dairy foods can protect against cancer, or increase the risk of cancer is not conclusive. Overall,
the proven health benefits of dairy foods greatly outweigh the unproven harm. Dairy foods should be encouraged as part
of a varied and nutritious diet as they are essential to maintain good bone and dental health, to prevent osteoporosis,
major cardiovascular disease risk factors, hypertension, type-2 diabetes, metabolic syndromes, as well as some cancers.
The Cancer Council and USDA recommend 3 servings of milk and milk products daily. This article reviews the potential
of milk and milk products (its indigenous or exogenous compounds) to inhibit different cancer risks. Also reviewed are
the reports over the years that have suggested milk and the dairy industry as responsible agents for causing cancer.
Introduction the most important components of the human diet, particularly
Cancer is a leading global cause of death and disability, respon- in the Western world, and increasingly also in Asia (Tsuda and
sible for approximately 7.6 million deaths each year. The fact that others 2000). Milk is considered to be the only foodstuff that con-
only 5% to 10% of all cancer cases are due to genetic defects and tains approximately all different substances known to be essential
that the remaining 90% to 95% are due to lifestyle factors (such as for human nutrition (Goodman and others 2002; Laakkonen and
smoking, diet and nutrition, alcohol, physical inactivity, obesity, Pukkala 2008). Milk is an important source of protein, calcium,
and sun exposure), infections, and environmental pollutants pro- and the B-group vitamins (thiamin, riboflavin, niacin, vitamin B6 ,
vides major opportunities for preventing cancer (La Vecchia and and folate), and provides vitamin A, vitamin C, magnesium, and
others 1991). Within the lifestyle factors, it is globally accepted zinc as well (Jelen 2005; Miller and others 2007). Carbohydrates
that nutrition and related factors play an important role in cancer are found in the form of lactose, which is generally considered
occurrence (Gonzalez and Riboli 2010). Observational evidence to be of low carcinogenicity. Also, approximately 1/3 of the fat
suggests that approximately 30% to 40% of cancer cases are poten- in whole milk is monounsaturated and small amounts of essen-
tially preventable via modification of nutritional factors and food tial fatty acids are provided. Milk is one of the major sources of
consumption patterns (Marmot and others 2007). conjugated linoleic acid (CLA) in the diet, although it is a minor
Milk and milk products are recognized as functional foods, sug- component of milk fat (Jelen 2005).
gesting that their use has a direct and significant effect on health Several milk constituents such as vitamin D, proteins, calcium,
outcomes and their consumption correlates with a reduced risk CLA, butyrate, saturated fatty acids, and contaminants such as
of numerous cancers (Keri Marshall 2004). Milk and other dairy pesticides, estrogen, and insulin-like growth factor I (IGF-I) may
products were recognized as important foods as early as 4000 BC, be responsible for either a prospective or a harmful association
evidenced by stone drawings from the Sahara desert. It is one of between dairy products and cancers (McCann and others 2004;
Moorman and Terry 2004; Parodi 2005; Bingham and Day 2006;
Cui and Rohan 2006; Laakkonen and Pukkala 2008). The main
compounds in milk and dairy products that might affect cancer
MS 20121243 Submitted 8/9/2012, Accepted 3/12/2012. Author Davoodi is can be classified in several groups and are shown in Figure 1.
with Dept. of Clinical Nutrition and Dietology, National Nutrition and Food Tech- This article reviews the preventive and inductive effects of dairy
nology Research Inst., Faculty of Nutrition Sciences, Food Science and Technology, products on the risk of cancers.
Shahid Beheshti Univ. of Medical Sciences, P.O. Box 19395-4741, Tehran, Iran.
Author Esmaeili is with Young Researchers Club, Varamin-Pishva Branch, Islamic
Azad Univ., Varamin, Iran. Author Mortazavian is with Dept. of Food Science Preventive Effects of Milk and Milk Products
and Technology, National Nutrition and Food Technology Research Inst., Faculty of Consumption on Cancer
Nutrition Sciences, Food Science and Technology, Shahid Beheshti Univ. of Medical
Sciences, P.O. Box 19395-4741 Tehran, Iran. Direct inquiries to author Mortazavian Effects of indigenous milk ingredients on cancer prevention
(E-mail: mortazvn@sbmu.ac.ir/mortazvn@yahoo.com) and Esmaeili (E-mail: The positive effects of indigenous milk and milk products on
saeideh.esmaeili@gmail.com). cancers and related mechanisms are discussed below and shown in
Figure 2.
C 2013 Institute of Food Technologists®
doi: 10.1111/1541-4337.12011 Vol. 12, 2013 r Comprehensive Reviews in Food Science and Food Safety 249Dairy products and cancer . . .
Milk
compounds
Exogenous compounds Indigenous compounds
of milk of milk
Vitamins Calcium
Contaminants
Minerals Chemical
CLA Proteins
Omega 3
Functional enriched Lactose
Phytochemical
compounds
Probiotics Vitamin D
Microbial Dairy additives
Synbiotic
Fats
Heating
Maillard Process-produced
IGF-1
Irradiation compound
Estrogens
Fermentation-
Bioactive peptides
produced compound
Figure 1–Main compounds in milk and dairy products that might affect cancer.
Colorectal cancer tations in the K-ras gene in rat colorectal neoplasms (Llor and
Colorectal cancer is the 3rd most common type of cancer world- others 1991; Aune and others 2012).
wide with about 1.2 million new cases diagnosed in 2008 account- Several clinical trials have reported reduced cell proliferation in
ing for 9.7% of all cancers (Ferlay and others 2010). An increased the colon and rectum with intake of calcium and dairy products
consumption of milk or dairy products is associated with a signif- (Holt and others 1998; Karagas and others 1998; Holt and others
icant reduction in colon cancer (Elwood and others 2008). Cho 2001; Ahearn and others 2011). Pooled data of dairy product in-
and others (2004a) conducted a large pooled analysis of data from take from 10 cohort studies demonstrated a 12% reduction in colon
10 cohorts (n = 534, 536) from 5 countries and found 4992 indi- cancer risk with each 500 mL increase in milk intake. There was
viduals diagnosed with colorectal cancer at follow-up. Individuals 17% reduction in colorectal cancer incidence with the ingestion
who consumed more than a glass of milk (≥250 g)/d had a 15% re- of Ricotta cheese greater than 25 mg/d (Cho and others 2004a,
duced risk of developing colorectal cancer (relative risk 0.85, 95% b). Epidemiologic intake and intervention studies have shown that
CI 0.78 to 0.94), compared to those who consumedDairy products and cancer . . .
Milk ingredients
compounds
Cancer Cancer Reducing cellular proliferation
induction prevention Enhancing cellular differentiation
Inhibiting metastasis
Tumorigenesis IGF-1 Vitamin D
Inducing apoptosis
Preventing cell adhesion and migration
Increasing
Modulating effect of calcium
mitotic activity
Estrogen
Increase DNA Conjugated linolenic acid Inducing expression of apoptosis
replication error
Potential Promote markers of Cell differentiation
Contaminants Butyrate Cellular apoptosis
carcinogenesis
Cell growth
Increasing
cell division Lactoferrin Anti-carcinogenic Protect from toxic bile acid
properties
Activating proto - Enhancement of apoptosis
Saturated
-oncogenes fatty acids Calcium Promotion of cellular differentiation
Except for
Decrease of cell proliferation
prostate cancer
Inactivating tumor
Mitigate against the mitogenic and
suppresser genes
Reduction in circulation antiapoptotic effects of PTH
of vitamin D
Figure 2–The effects of indigenous milk ingredients on cancers with related mechanisms.
Some fat components of dairy products, including CLA and animals and in vitro have shown protective effects of CLA against
butyric acid (Liew and others 1995), have been proved to be carcinogenesis in the mammary gland, potentially by inhibiting
protective in experimental studies (Hague and Paraskeva 1995; the cyclooxygenase-2 or the lipo-oxygenase pathway or by induc-
Parodi 1997). The results of a Cohort study in Swedish women ing the expression of apoptotic genes (Kelley and others 2007). In
showed the women who consumed ≥4 servings of high-fat dairy the Nurses’ Health Study II (Cho and others 2003), women with
a high consumption of low-fat dairy products during their pre-
foods per day (including whole milk, full-fat cultured milk, cheese,
cream, sour cream, and butter) had a multivariate rate ratio of menopausal years had a nonsignificant negative association with
colorectal cancer of 0.59 (95% CI: 0.44, 0.79; P for trend = 0.002)
breast cancer risk. The findings of a meta-analysis of prospective
when compared to the women who consumedDairy products and cancer . . .
calcium intakes protect against breast cancer, particularly in pre- hormone (PTH) production (Grant 2007). Hence, by downregu-
menopausal women (Chen and others 2010). The results of a large lating PTH production, calcium potentially mitigates against the
cohort study showed women with the highest intake of dietary mitogenic and antiapoptotic effects of PTH. The findings of a
calcium (>1250 mg/d) were at a lower risk of breast cancer than case-control study indicated that low-fat milk consumption was
those reporting ≤500 mg/d [RR, 0.80; 95% confidence interval inversely associated with risk of ovarian cancer (Toriola and others
(95% CI), 0.67 to 0.95; P = 0.02] (McCullough and others 2005). 2010).
The results of latter study support the theory that dietary calcium
and/or some other components in dairy products may reduce the Bladder cancer
risk of postmenopausal breast cancer. Bladder cancer is the 9th most common malignancy worldwide
Proteins and peptides existing in milk have been reported to be (Parkin and others 2005). A role of diet and nutrition in blad-
cancer preventive agents (Knekt and others 1996; Tsuda and others der carcinogenesis is plausible since most substances or metabo-
2000; Wakabayashi and others 2006; Rodrigues and others 2008). lites, including carcinogens, are excreted through the urinary tract
For example, lactoferrin (LF) that is also known for its inhibitory (Vecchia and Negri 1996; Larsson and others 2008). Consump-
action on cell proliferation as well as for its anti-inflammatory tion of milk and dairy products has been associated with decreased
and antioxidant abilities (Tsuda and others 2002; Ward and others bladder cancer incidence. Meta-analyses of cohort data available
2005; Rodrigues and others 2008; Iigo and others 2009. LF is to date support an inverse association between milk intake and
an iron-binding glycoprotein from the transferrin family. In vivo risk of colorectal and bladder cancers (Vecchia and Negri 1996;
studies showed that oral administration of bovine LF to rodents Lampe 2011). It has been declared that consumption of skim milk
significantly reduces chemically induced carcinogenesis in different and fermented milk with a low-fat content is inversely and whole
organs (breast, esophagus, tongue, lung, liver, colon, and bladder) milk with a high-fat content is positively associated with risk of
and inhibits angiogenesis (Tsuda and others 2002; Iigo and others bladder cancer (Mao and others 2011). Casein is the major pro-
2009). Although the mechanisms of LF action are still not fully tein in skim milk powder and can display comparative anticancer
understood, there is evidence representing its ability to interact activity (McIntosh and others 1995). In laboratory animals, whey-
with some receptors, as well as to modulate genetic expression containing diets have been shown to reduce colon and mammary
of several molecules that are vital to the cell cycle and apoptosis cancers (Hakkak and others 2001; McIntosh and Le Leu 2001).
machinery.
Prostate cancer
Ovarian cancer Prostate cancer (PCa) is the 2nd leading cause of cancer in
Ovarian cancer has the highest mortality rate of all the gy- males (Greenlee and others 2000). While genetic factors have been
necological cancers and is the 4th leading cause of death from shown to play a role in the development of hereditary prostate can-
cancer in women (Lefkowitz and Garland 1994). There is great cer (HPC) (Nwosu and others 2001; Carpten and others 2002;
interest in the possibility that vitamin D might be a broad- Rökman and others 2002), the protective effects and/or thera-
spectrum antineoplastic substance (Giovannucci 2005). Ovarian peutic benefits of various dietary substances have only recently
cancer is one of the malignant diseases that has been linked to been unraveled (Chan and others 1998; Blumenfeld and oth-
vitamin D (Lefkowitz and Garland 1994; Grant 2003). There are ers 2000; Schmitz-Drager and others 2001; Schulman and others
evidences that the ovarian epithelium contains receptors for the 2001; Jankevicius and others 2002).
active form of vitamin D (Saunders and others 1992) and in vitro Interest in vitamin D as a preventive agent for prostate cancer
studies have shown that growth of ovarian carcinoma cells can comes from several epidemiologic observations (Jemal and others
be inhibited by vitamin D and its analogues (Saunders and others 2004). Laboratory evidences indicate that high circulating lev-
1995; Friedrich and others 2003). Dietary studies suggest a role for els of vitamin D and its active metabolite 1,25(OH)2 -vitamin D
vitamin D and calcium in the prevention of ovarian cancer (Toriola (1,25(OH)2 D) (500- to 1000-fold more active than vitamin D)
and others 2010). There are biological reasons to suspect that the inhibit prostate carcinogenesis in vitro by reducing prostate cel-
active form of vitamin D, 1,25-(OH)2 D (Brommage and Deluca lular proliferation and enhancing cellular differentiation (Reichel
1985) may be related to ovarian cancer incidence and mortality. and others 1989; Klein 2005). Also, induced apoptosis (Blutt and
For example, the vitamin D nuclear receptor, which mediates the others 2000) prevented cell adhesion and migration (Sung and
effect of 1,25-(OH) 2 D (3 : 34), is found in human ovarian tumor Feldman 2000) and inhibited metastasis (Lokeshwar and others
specimens and cell lines (Saunders and others 1992; Ahonen and 1999), although dietary intakes of dairy products rich in calcium,
others 2000; Villena-Heinsen and others 2002). Moreover, 1,25- which depresses serum level of vitamin D, are associated with a
(OH)2 D (Brommage and Deluca 1985) inhibits cell proliferation higher risk of prostate cancer (Thompson and others 2003; Parodi
in ovarian cancer cell lines (Saunders and others 1995; Ahonen 2009). There are a number of components in milk fat, such as
and others 2000) and induces apoptosis (Jiang and others 2004). sphingolipids, CLA, butyric acid, branched-chain fatty acids, and
An inverse relationship between dietary calcium and ovarian the fat-soluble vitamins, which in animal models have exhibited
cancer has been reported in some studies but not all (Kushi anticancer action (Parodi 1999; Parodi 2008). Milk proteins have
and others 1999; Bidoli and others 2001; Goodman and oth- also been shown to have anticancer properties (Parodi 2007).
ers 2002; Genkinger and others 2006; Koralek and others 2006; Various studies indicate that milk protein, such as casein and
Park and others 2009). Though the biological processes by which especially whey proteins, may protect against some cancers such
calcium may influence ovarian cancer are largely unknown, pos- as colon, breast, and prostate gland (Parodi 2007). The anticancer
sible mechanisms include: a) the effects of calcium on apoptosis, properties of bovine whey proteins may be attributed to their abil-
cell growth, and proliferation (McConkey and Orrenius 1997; ity to increase cellular levels of glutathione, an antioxidant. Also,
Ramasamy 2006), b) effects of the calcium receptor (CaR) on whey proteins may reduce cancer risk by enhancing hormonal and
cell proliferation and differentiation (Rodland 2004; Ramasamy cell-mediated immune responses (Parodi 1998; Bounous 2000;
2006) and c) effects of calcium on down-regulating parathyroid Micke and others 2001; Parodi 2001; Eliassen and others 2002;
252 Comprehensive Reviews in Food Science and Food Safety r Vol. 12, 2013
C 2013 Institute of Food Technologists®Dairy products and cancer . . .
Table 1–Selected publications on cancer prevention of indigenous compounds of milk and milk product.
Reference Note Type of cancer Type of product
(Larsson and others 2008) Women and men who consumed ≥2 servings of cultured milk per Bladder Cultured milk
day had a 38% lower risk of bladder cancer than did those who
never consumed cultured milk.
(Larsson and others 2005) A significantly (53%) decreased risk of death due to bladder cancer Bladder Milk
among Japanese men and women who consumed milk almost
every day in comparison with those who consumed 2 servings
milk/month.
(Rayes and others 2008) Protective effect of natural fermented milk (NFM) containing Liver Fermented milk
Lactobacillus spp. and Bifidobacterium spp. against cancer of the
liver.
(Cox and Sneyd 2011) Regular daily consumption of milk in childhood may reduce Colorectal Milk and dairy foods
colorectal cancer incidence. Participation in school milk programs
in New Zealand was associated with a 2.1% reduction (95% C I:
0 .7, 3. 5) in the odds ratio for colorectal cancer for every 100
half-pint bottles drunk (1 half-pint bottle = 284 mL).
(Larsson and others 2005) Swedish women who consumed ≥4 servings of high-fat dairy foods Colorectal Dairy foods
per day (including whole milk, full-fat cultured milk, cheese,
cream, sour cream, and butter) had a multivariate rate ratio of
colorectal cancer of 0.59 (95% CI: 0.44, 0.79; P for trend = 0.002)
when compared with the women who consumedDairy products and cancer . . .
Iron deficiency is a common nutritional deficiency worldwide, to probiotic yogurt and its chemical, mirobiological, and sensory
affecting mainly older infants, young children, and women of child characteristics (Heydari and others 2011). Mohammadi and Mor-
bearing age. Dairy products are an important source of nutrients tazavian (2010) reviewed the technological aspects of prebiotics in
but are low in iron. Fortification of these products can increase probiotic fermented milk (Mohammadi and Mortazavian 2010).
average dietary iron intake (Zhang and Mahoney 1989). Dairy Microalgae (cyanobacterial biomass) may be added into fer-
products that are often fortified with iron are cheddar cheese, mented milk in order to increase the functional characteristics of
brown whey cheese, mozzarella cheese, white soft cheese, baker’s the product (Varga and others 2002). Spirulina and chlorella are
and cottage cheese, Harvatti cheese, yogurt (nonfat and low fat), blue–green microalgae that contain high antioxidant constituents,
and chocolate milk (Zhang and Mahoney 1991; Biebinger and multiple amino acids, high-quality proteins, Fe, Ca, unsaturated
others 2008). fatty acids, and many vitamins including A, B2 , B6 , B9 , B12 , E,
Zinc is necessary for the activity of over 100 specific enzymes and K. They have antiviral, anti-inflammatory, and antitumoral ef-
that are involved in major metabolic pathways, including physical fects and reduce blood lipid profile, blood sugar, body weight, and
growth, immune competence, reproductive function, and neu- wound healing time (Gyenis and others 2005). Beheshtipour and
robehavioral development. Zinc-fortified cheddar cheese could be others (2012) considered adding microalgae to probiotic yogurt
an excellent food source for replenishment of zinc levels in groups based on its chemical, mirobiological, and sensory characteristics
at risk of zinc deficiency (Biebinger and others 2008; Kahraman (Beheshtipour and others 2012).
and Ustunol 2012).
Evidence demonstrates that current vitamin D intakes in adults
are inadequate (Vieth 2001). Several studies suggest that higher
serum vitamin D concentrations are associated with lower rates of Functional Microbial-Enriched Compounds
breast, ovarian, prostate, and colorectal cancers, as well as decreased Probiotics
risk of developing multiple sclerosis (Vieth 2001). Therefore, for- Probiotic products contain at least one living probiotic
tification of fluid milk, cheese, yogurt, fermented dairy beverages, strain that beneficially affects the host by improving intesti-
and ice cream with vitamin D3 is an important public health pro- nal microbial balance (Giboson and Roberfroid 1995; Biström
gram (Kazmi and others 2007). and Nordström 2002. The most common species of bac-
Vitamin A is a fat-soluble vitamin and represents a group of teria used in probiotic dairy foods include L. acidophilus,
substances necessary for reproduction, cellular differentiation, the L. johnsonii, L. gasseri, L. crispatus, L. casei, L. paracasei, L. rhamnosus,
immune system, gene regulation, and eye sight. The fortification L. reuteri, L. plantarum, Bifidobacterium lactis, B. bifidum, B. infantis,
of whole milk with vitamin A is voluntary, whereas fortification B. breve, B. animalis, and B. adolescentis (Kennedy and Bandaiphet
of low fat milk and skim milk is strongly recommended and even 2004).
mandatory in some countries because of the removal with cream There are several epidemiological studies that support the
of fat-soluble vitamins during centrifugations. protective role of probiotics against cancers (Commane and others
The protective role of folic acid in the reduction of neural 2005). Consumption of fermented dairy products with LAB
tube defects, coronary heart diseases, and cancer has been recog- may elicit antitumor effects. Studies on the effect of probiotic
nized (Gangadharan and Nampoothiri 2011). Folic acid has also consumption on cancer appear promising, since recent in vitro
been shown to reduce the risk of colorectal and breast cancers and in vivo studies have indicated that probiotic bacteria may
(Prinz-Langenohl and others 2001). Milk and fermented dairy reduce the risk, incidence, and number of tumors of the colon,
products represent a good source of natural folate and folate- liver, breast, and bladder (de Moreno de LeBlanc and Perdigón
binding proteins that improve the bioavailability and stability of 2010; Kumar and others 2010a). The protective impact against
folate (Gangadharan and Nampoothiri 2011). Folic acid can be cancer development may be ascribed to binding of mutagens
added successfully in plain yogurt up to the recommended daily by intestinal bacteria (Kumar and others 2010a; Kumar and
allowance of 400 μg (Boeneke and Aryana 2007). others 2012). Probiotics may suppress the growth of bacteria
CLA exerts a strong positive influence on human health, but its that convert procarcinogenic compounds into carcinogenic
intake is typically too low, and increased consumption of CLA is compounds and thereby reducing the amount of carcinogens
recommended. A good way to increase the CLA content in the diet in the intestine, reducing the enzymes beta-glucuronidase and
without a change in eating habits is enrichment of commonly con- beta-glucosidase and deconjugation of bile acids, or by enhancing
sumed food products with CLA supplements (Rodrı́guez-Alcalá the immune system of the host (de Moreno de LeBlanc and
and Fontecha 2007). Many studies have demonstrated the feasi- Perdigón 2010). There are reports that administration of lactic
bility of producing CLA-enriched dairy products with acceptable acid bacteria (LAB) results in increased activity of antioxidative
sensory characteristics and shelf life (Jones and others 2005). enzymes or modulating circulatory oxidative stress that protects
Prebiotic products contain a prebiotic (nondigestible) ingredi- cells against carcinogen-induced damage (Burns and Rowland
ent that beneficially affects the host by selectively stimulating the 2000; Hirayama and Rafter 2000; Karimi and others 2011; Kumar
growth and/or activity of colonic probiotic bacteria (Mohammadi and others 2011; Mohammadi and Mortazavian 2011).
and others 2012). They are not digested in the upper gastrointesti- A “symbiotic” product contains both probiotics and prebiotics
nal tract, because of the inability of the digestive enzymes. They are that beneficially affect the host by improving the survival and/or
digested in the colon (Schrezenmeir and de Vrese 2001). The end activity of probiotic bacteria in the gastrointestinal tract (Kennedy
products in the gut fermentation are mainly short chain fatty acids and Bandaiphet 2004; Cruz and others 2010). Possible mecha-
(propionic and butyric acid), lactic acid, acetic acid, hydrogen, nisms by which synbiotics manifest anticancer activity include a
methane, and carbon dioxide. Short chain fatty acids, especially change in gut pH, modulation of immune response, decreased
butyric acid, are known to act as an energy source for enterocytes colonic inflammation, antimutagenic properties, antioxidant
(Wollowski and others 2001). Heydari and others (2011) have properties, production of antitumorigenic compounds, and re-
investigated the effects of adding different prebiotic compounds duction of carcinogenic compounds (Cho 2010).
254 Comprehensive Reviews in Food Science and Food Safety r Vol. 12, 2013
C 2013 Institute of Food Technologists®Dairy products and cancer . . . Fermentation-Produced Compounds Cancer-Induced Effects of Milk and Milk Products Fermentation of milk can exert preventive effects on cancer Effects of indigenous milk ingredients on cancer induction due to the bacterial cells of starter cultures or their metabolites. Prostate cancer. A collection of cancer rates and food supply The positive roles of starter cultures are significantly enhanced data from 42 countries revealed that milk was the food most closely when probiotics are used. Fermented dairy products contain live correlated with this cancer incidence (r = 0.711) and mortality (r = LAB, and these bacteria and their metabolites have been shown to 0.766) (Ganmaa and others 2002). A quantitative analysis for the modulate the immune response in animals (Kato and others 1994; published cohort studies suggested a statistically significant 10% Matsuzaki 1998; Kato and others 1999), suppress carcinogenesis increase of prostate cancer risk for the consumption of milk and in rodents (Kato and others 1994; Lim and others 2002), inhibit dairy products (Qin and others 2007). In addition, a recent meta- the activity of enzymes related to carcinogenesis (Spanhaak and analysis of prospective studies reported that men with the highest others 1998), and bind mutagenic and carcinogenic heterocyclic intake of calcium had a 39% higher risk of prostate cancer than amines (Knasmüller and others 2001). Also, a major component those with the lowest intake (Gao and others 2005). These find- of milk and milk products that can possibly mediate association ings suggest that excessive consumption of milk and dairy products with cancer risk is lactose. The fermentation process leads to a increases the risk of prostate cancer. Gao and others (2005) quanti- reduction of the lactose content of milk and an increase in lactic fied a dose-response model, indicating that, in adult males, intake acid (Keszei and others 2010). of 3 servings per day of dairy products was associated with about a Bioactive peptides can be generated by the starter cultures 9% increase in risk of prostate cancer compared with current (U.S.) used in the manufacture of fermented dairy products. The pro- average intake of 1.8 servings per day (a serving equates to 244 g teolytic systems of LAB, especially of Lactococcus lactis, Lactobacil- milk or yogurt, 43 g cheese, 5 g butter, or 132 g ice cream) (Givens lus helveticus, and L. delbrueckii ssp. bulgaricus, are well character- and others 2008). Parodi (2009) indicated that high consumption ized. Some articles have reviewed the release of various bioactive of calcium in the diet could be a factor for the role of dairy prod- peptides from milk proteins through microbial proteolysis (Matar ucts in prostate cancer (Parodi 2009).The findings of a case-control and others 1996; Pihlanto-Leppälä and others 1998). The milk- cohort study showed that men who consumed more than 2000 mg derived bioactive peptides include antithrombotic (Bal dit Sollier of calcium had a RR of 4.6 (95% CI = 1.9 to 11.0) for metastatic and others 1996), antihypertensive (Seppo and others 2003), im- and fatal prostate cancer compared with men consuming less than munomodulating (Laffineur and others 1996), antioxidative (San- 500 mg (Giovannucci and others 1998). As a mechanism, some drine and others 2001), antimicrobial (Saito and others 1994), researchers proposed that high calcium intake suppressed the con- anticancer (Parodi 2007), mineral carrying (Meisel and FitzGerald version of 25(OH) vitamin D to 1,25(OH)2 vitamin D that has an 2003), and growth-promoting properties (Parodi 2007). In vitro antitumor effect against prostate cancer (Veierød and others 1997; studies indicate that casein-derived peptides isolated from the mi- Giovannucci 1998; Schuurman and others 1999; Chan and others crobial fermentation of milk inhibit colon cancer by altering cell 2000; Giovannucci and others 2006; Li and others 2007). kinetics (MacDonald and others 1994). Dietary fat has been reported to increase the androgen level The findings of a large prospective study of Swedish women associated with prostate cancer risk (Dorgan and others 1996; and men indicated that a high intake of cultured milk was cor- Fleshner and others 2004). Also, high intake of animal fat has related with a significantly lower risk of bladder cancer. Women been associated with increased testosterone levels (Dorgan and and men who consumed ≥2 servings of cultured milk per day others 1996) and this may lead to increased cell division, acti- had a 38% lower risk of bladder cancer than did those who never vation of proto-oncogenes, and inactivation of tumor suppressor consumed cultured milk (Larsson and others 2008). The probiotic genes (Ross and Henderson 1994); and high testosterone levels strains of E. faecium RM11 and L. fermentum RM28 also triggered may influence prostate cancer risk (Gann and others 1996). The antiproliferation of colon cancer cells at rates of 21% to 29% and results of a population-based prospective study in 43435 Japanese 22% to 29%, respectively (Thirabunyanon and others 2009). The men indicated that specific saturated fatty acids in dairy foods, results of a large Japanese case-control study on intake of LAB myristic acid and palmitic acid, increased the risk of prostate can- suggested that the habitual intake of fermented milk with the cer in a dose-dependent manner (Kurahashi and others 2008). LcS strain reduces the risk of bladder cancer in the population However, a large prospective study in a prostate cancer screen- (Ohashi and others 2002). Numerous studies reported an inverse ing trial about dairy products also showed that low fat types may correlation between cultured milk consumption and risk of vari- be modestly associated with increased risks for prostate cancer. ous kinds of cancers such as colon, bladder, liver, and breast (Aso The authors argued that removal of fat from milk may remove and Akazan 1992; Tomita and others 1994; Aso and others 1995; other components with potentially cancer-protective properties, Lim and others 2002; Radosavljević and others 2003; Larsson and such as CLA. Also, low-fat milk generally contains higher levels of others 2008; Rayes and others 2008; Thirabunyanon and others calcium (Bodner-Montville and others 2006) that, as mentioned 2009; Keszei and others 2010; Kumar and others 2010a,b; Ahearn above, may increase the risk of cancer (Ahn and others 2007). Cur- and others 2011; Kumar and others 2012). LAB ferments lac- rent dietary guidelines for cancer prevention encourage meeting tose of milk into lactic acid (pH reduction) and flavor compounds recommended intake by choosing low-fat or nonfat dairy foods such as acetaldehyde and diacetyl. Carbon dioxide is among the (Kushi and others 2006). Subgroup analyses of dairy products forms of other possible produced compounds. The aforemen- such as whole milk, low-fat milk, skim milk, cheese, and yogurt tioned compounds inhibit the growth of most other bacteria found that the only significant positive correlation was between present in a safe and nutritious product. Fermented milk, espe- high intake of skim milk and risk of advanced prostate cancer, cially yogurt, is considered to be both safe and nutritious (Fonden with an RR of 1.23 (0.99 to 1.54) (Parodi 2009). A number of and others 2003). The useful impact of fermented milk on can- studies found that high intake of skim milk, but not whole milk, cer prevention is enhanced by the presence/addition of probiotic was associated with an increased risk of prostate cancer (Parodi bacteria. 2009). C 2013 Institute of Food Technologists® Vol. 12, 2013 r Comprehensive Reviews in Food Science and Food Safety 255
Dairy products and cancer . . . Androgens and estrogen are affected by fat intake (Hill and oth- women with galactosemia (Kaufman and others 1981) that arises ers 1980; Hämäläinen and others 1984). Additionally, milk itself from an autosomal recessive defect in the galactose-1-phosphate contains considerable amounts of estrogens due to the fact that uridyl transferase (GALT) gene (Larsson and others 2006a). Im- commercial milk is mainly produced by pregnant cows in devel- pairment of the GALT gene might lead to an accumulation of oped countries. Because 17β-estradiol, an estrogen, is a carcinogen galactose and other metabolites in the body, including the ovaries for prostate cancer, estrogen contained in milk and enhanced by (Larsson and others 2006a). milk fat should not be ignored when considering milk as a risk fac- The results of a pooled analysis of 12 cohort studies showed tor for prostate cancer (Ganmaa and others 2004; Qin and others that higher lactose intakes comparing ≥30 compared with 10 g/d 2004a, b). were associated with a statistically significant higher risk of ovarian Cow milk contains high levels of IGF-I that plays an important cancer, although the trend was not statistically significant (pooled role in the regulation of cell proliferation, differentiation, apopto- multivariate relative risk, 1.19; 95% confidence interval, 1.01 to sis, and neoplasia (Jones and Clemmons 1995; Yu and Rohan 2000; 1.40; P trend = 0.19) (Genkinger and others 2006). This study Jerome and others 2003; Pollak and others 2004), and may con- showed a modest elevation in the risk of ovarian cancer for lactose tribute to prostate cancer risk (Cadogan and others 1997; Holmes intake equivalent to 3 or more servings of milk per day. The find- and others 2002; Renehan and others 2004; Hoppe and others ings from prospective cohort studies, but not case-control studies, 2006; Parodi 2009). In a human study, plasma IGF-I concentra- revealed that high intakes of dairy foods and lactose may increase tion increased by 10% when healthy subjects consumed cow milk the risk of ovarian cancer (Larsson and others 2006a). (Heaney and others 1999). The high levels of estrogen and IGF-I Breast cancer. The major hypotheses that suggest an increased in milk were considered to be responsible for this effect (Qin and risk of breast cancer risk associated with the consumption of dairy others 2004b). products include the following: Ovarian cancer. The results of an experiment conducted with (1) A high consumption of dairy products may reflect an overall a Swedish mammography cohort showed a correlation between high dietary fat intake, particularly saturated fat, which, in ovarian cancer risk and the quantity of milk consumed. Women turn, has been associated with breast cancer risk. Total dairy who consumed ≥4 servings of total dairy products per day doubled intake was nonsignificantly associated, and high-fat dairy their risk of ovarian cancer compared to women who consumed intake was positively associated with risk (Parodi 2005). Al-
Dairy products and cancer . . .
Table 2–Selected publications on cancer induction of indigenous milk and milk product compounds.
Reference Note Type of cancer Type of product
(Qin and others 2007) A statistically significant 10% increase of prostate cancer risk for the Prostate Milk and products
consumption of milk and dairy products
(Gao and others 2005) Intakes of 3 servings per day of dairy products were associated with Prostate Dairy products
about a 9% increase in risk of prostate cancer compared with current
(U.S.) average intakes of 1.8 servings per day (a serving equates to
244 g milk or yogurt, 43 g cheese, 5 g butter, or 132 g ice cream)
(Farlow and others 2009) Women who consumed ≥4 servings of total dairy products per day Ovarian Total dairy
doubled their risk of serious ovarian cancer compared to women who products
consumedDairy products and cancer . . .
toxic action of melamine is the kidneys and the urinary tract. Levels long-term, even in low-level, exposure to inorganic arsenic is
of melamine reported in dairy products (including infant formula) related to increased risk of cancer in the lung, skin, bladder, and
ranged from 0.09 to 6200 mg/kg (Fischer and others 2011). possibly, other sites. Also, developmental arsenic exposure may
Mycotoxins. Dairy contamination by mycotoxins can be via lead to increases in pancreatic and hematopoietic cancer (Yorifuji
fungus-infested (moldy) feedstuffs consumed by dairy animals. and others 2010, 2011).
Aflatoxin M1 (AFM1 ) is the hydroxylated metabolite of afla- Nitrates/nitrites are from other environmental contaminations
toxin B1 (AFB1 ) and can be found in milk and subsequently that may be found in milk and milk products. Raw milk typi-
in other dairy products when lactating animals are fed with cally contains 1 to 5 mg/L of nitrate and ≤0.01 mg/L of nitrite.
mold-contaminated feedstuffs. Mammals that ingest aflatoxin Postsecretory contamination with nitrate is possible during milk
B1 (AFB1 )-contaminated diets excrete amounts of the principal collection and processing. Nitric acid can be used to sanitize dairy
4-hydroxylated metabolite known as aflatoxin M1 into milk factory equipment so that inadvertent incorporation of NO3 is
(Prandini and others 2009). possible. The other significant source of contamination is incom-
Aflatoxins are toxic, carcinogenic, and/or teratogenic to hu- ing wash-water or added water used for powder reconstitution
mans and animals. AFM1 is relatively stable in raw and processed or in other addition in certain products. Hence, modern facto-
milk products and is not destroyed by regular heat treatments in- ries focus on water purification by deionization. Moreover, nitrate
cluding pasteurization. The International Agency for Research on contamination of dried milk products is significantly more likely
Cancer (1994) classified AFB1 as a class 1 human carcinogen and indirectly with heated spray dryers as compared to indirect steam-
AFM1 as a class 2B possible human carcinogen (Cathey and others heated systems, as a consequence of fuel gas combustion products
1994; Galvano and others 1996; Moss 2002). AFM1 is cytotoxic, responsible for the formation of nitrogen oxides. Also, in the for-
as demonstrated in human hepatocytes in vitro and its acute tox- mulation of certain cheeses, nitrate is added in small quantities
icity in several species is similar to that of AFB1 . AFM1 can also (20 to 30 mg/kg bulk milk) to restrict late blowing and defects
cause DNA damage, gene mutation, chromosomal anomalies, and associated with bacterial gas formation. However, nitrate in fresh
cell transformation in mammalians cells in vitro, in insects, lower cheese is very unstable and is rapidly reduced to nitrite by milk
eukaryotes, and bacteria (Prandini and others 2009). Overall, the xanthine oxidase and various microbial nitrate reductases during
occurrence of AFM1 in milk makes it a particular risk for humans cheese maturation. Therefore, its content in cheese is typically
because it has both chronic and acute effects on human health. The very low (Indyk and Woollard 2011). Most previous investigations
acute symptoms of aflatoxins include vomiting, diarrhea, pyrexia, into the association between nitrate and nitrite and human cancer
and abdominal pain. The chronic symptoms are related to liver have focused on gastrointestinal cancers, although the relationship
cancer, hepatitis, jaundice, hepatomegaly, and cirrhosis (Turner with thyroid cancer risk is biologically plausible (Forman 1989;
and others 2000). It has been reported that aflatoxins may also Boeing 1991; Van Loon and others 1997). A positive association
play a role in Reye’s syndrome, kwashiorkor, and suppressing between nitrate intake and thyroid cancer was recently reported
of the immune system that, in turn, increases disease incidence in the Iowa Women’s Health Study (Ward and others 2010).
(Scudamore 1998).
Other environmental contaminants. Dioxins are formed as Process-Produced Compounds in Dairy Products
inadvertent by-products in many chemical processes involving During the processing of milk and milk products, as well as dur-
chlorine and in any combustion process. Dioxins are very ing storage time, numerous compounds are produced or changed
potent toxicants. The known toxic effects of dioxin include that could associate with different types of cancer. Severe heat-
dermal toxicity, immunotoxicity, reproductive abnormalities, ing in the dairy industry and exposure to sunlight are the most
teratogenicity, endocrine disruption, and carcinogenicity. Dairy important factors that could produce changes in dairy ingredients
products contribute about 1/4 to 1/2 to the dietary intake of (such as proteins, fats, carbohydrates, and vitamins) and generate
total dioxins (Bhandari and others 2005). compounds with carcinogenic and mutagenic potential. Improper
Polychlorinated biphenyls (PCBs) are chlorinated hydrocar- reactions such as pyrolysis, fat oxidation, and the Maillard reaction
bons, the manufacture, processing, and distribution of PCBs have can noticeably be intensified by elevated temperatures.
been prohibited in almost all industrial countries since the late High-fat and creamy dairy products (such as some types of yo-
1980s, their entry into the environment may still occur, especially gurt, cheeses, and desserts) are susceptible to fat auto-oxidation and
due to improper disposal practices or leaks from electrical equip- photo-oxidation and the oxidation reactions can lead to formation
ment (such as transformers) and hydraulic systems still in use. PCBs of free radicals and polymerized compounds that are carcinogenic
are of great health concern and can cause a variety of adverse ef- (Belitz and others 2004). Severe heat treatments enhance fat oxi-
fects. PCBs have been classified as probable human carcinogens. In dation.
animal studies, PCBs have exhibited reproductive, developmen- The Maillard reaction has considerable consequences on the
tal, and immunotoxic effects. Therefore, many countries have set quality of heated milk and milk products in terms of color, fla-
maximum residue limits for PCBs in dairy products (Fischer and vor, and nutritional value, and probable toxic compounds. Also,
others 2011). some Maillard reaction products can enter oxidative reactions (van
Heavy metals elements find their way into milk through several Boekel 1998).
routes. Elements such as chromium and nickel from stainless steel Heat treatments and homogenization of milk causes oxidation of
dairy equipment or tin from soldered cans may enter milk through valuable anticancer CLA through exposure to high temperatures,
direct contact. Heavy metals such as cadmium, lead, mercury, and high pressures, and reduction of fat globule size (Norgauer 2005).
arsenic are not expected to have any direct contact with milk and Cholesterol oxidation products (COPs) are found in dairy prod-
milk products except in accidental cases. For these elements, the ucts. Published results have suggested that the content of COPs
main pathway to milk is through the ingestion of contaminated in milk and dairy products is very small. Formation of COPs in
feed and water by milk-producing animals (Fischer and others milk and milk products can only occur under harsh conditions
2011). The findings of previous studies have demonstrated that such as the application of high heating temperatures for a long
258 Comprehensive Reviews in Food Science and Food Safety r Vol. 12, 2013
C 2013 Institute of Food Technologists®Dairy products and cancer . . .
period or long storage at high temperatures, and in the case of (and illegally) contaminated with environmental pollutants or cer-
foods in the dehydrated state or at low water activities. In addi- tain toxicants could spell harm to human health.
tion, powdered milk contains oxidized cholesterol, a product that
further contributes to the oxidative stress in those who consume
the milk (Bösinger and others 1993; Guardiola and others 1996; References
Linseisen and Wolfram 1998; O’Brien and others 2000). COPs Ahearn TU, McCullough ML, Flanders WD, Long Q, Sidelnikov E, Fedirko
have many biological effects such as atherogenic (Imai and others V, Daniel CR, Rutherford RE, Shaukat A, Bostick RM. 2011. A
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