Is There a Link between a High-Fat Diet during Puberty and Breast Cancer Risk?

“…increased prepubertal BMI is highly associated with early pubertal maturation and the onset of menses – known risk factors for breast cancer.”

Recent data demonstrated that 19% of US children aged 6–11 years of age are overweight, as defined by being over the 95th percentile for their age in BMI [1]. The typical western diet, high in saturated fat, is largely credited for the obesity epidemic in the USA. However, it should be noted that there are more people who eat a high-fat western diet and potentially suffer its consequences, than are actually obese. Ample literature is available showing that the dietary habits that lead to overweight and obesity correlate with the onset of diabetes and heart disease later in life [2].

“…studies are needed to assess dietary influences on hormonal levels, particularly during puberty given the association of early puberty with increased breast cancer risk.”

Obesity and being overweight are also implicated in the etiology of breast cancer. Prepubertal overweight and obesity are at the forefront of suspected contributors to early puberty [3] and early puberty is clearly a risk factor for breast cancer [4]. Studies have established that girls with higher BMIs are likely to experience puberty at an earlier age [5], but the mechanisms by which this occurs are not well understood. An important gap in our understanding is how diet specifically influences pubertal breast development. At the same time, the effects of diet versus those of increased BMI are difficult to distinguish, since a high-fat diet (HFD) often results in increased BMI. While very little is known about how diet versus childhood obesity affects an individual's future risk for breast cancer, it is acknowledged that the relationship of diet, weight status and weight gain in childhood deserves further attention [6]. In this regard, animal studies offer a number of advantages for elucidating the underlying mechanisms of the effects of a HFD and distinguishing between the effects of a HFD and obesity at a given age/developmental stage (i.e., puberty or adulthood) on mammary cancer susceptibility. Many studies in rodents, in a variety of breast cancer models, consistently demonstrate increased mammary tumorigenesis in animals fed a HFD without the confounding effects of obesity. For example, a HFD can increase the numbers of mammary tumors in transgenic MMTV-HER2/Neu mice with little weight gain [7] and fatless transgenic A-Zip/F-1 mice show increased mammary tumorigenesis, while being diabetic with expression of many inflammatory products that promote tumor progression [8]. It was also found that HFD can enhance mammary tumorigenesis in transgenic MMTV-TGF-a mice without obesity [9]. Thus, the expansion of adipose mass associated with obesity need not be the source of inflammatory factors promoting tumorigenesis in the metabolic syndrome. Even more compelling is that human epidemiological studies have demonstrated that a HFD in itself is a risk factor for breast cancer [10].

In the USA and western Europe, increased BMI and obesity are largely attributable to the consumption of a ‘western diet’ high in saturated fat. The literature supporting the notion that a HFD can enhance tumorigenesis without obesity has implications for the broader population that consumes a HFD without becoming obese. Among the mechanisms proposed for obesity-associated breast cancer risk, are altered glucose metabolism, altered steroid hormone levels and inflammatory processes [11]. It is entirely possible that a HFD during puberty may alter breast development, independently of increasing BMI, through one or more of these mechanisms, thereby modifying the risk for breast cancer.

A chronic HFD can induce insulin resistance [11]. The resulting chronic hyperinsulinemia and increased availability of IGF-1 may stimulate tumor growth. However, epidemiological studies on the association of heightened levels of IGF-1 with breast cancer incidence have come down on both sides of this issue.

The exact mechanisms through which hormonal factors increase breast cancer risk remain unknown. However, the ovarian hormones, estrogen and progesterone are believed to play an important role in the etiology of breast cancer. Progesterone in combination with estrogen is a potent mitogen in the human breast [12] and in animal models [13,14]. Recent studies have shown that exogenous progestins, used in combination with estrogens in menopausal HRT, increase breast cancer risk, whereas estrogen-alone HRT is not associated with an increase [15]. In this regard, it is notable that the recent decrease in breast cancer incidence has been attributed to the decreased use of combined estrogen plus progestin HRT [16]. Adipose tissue is an endogenous source of estrogen through the activity of aromatases and this is the major source of estrogen in postmenopausal women [11]. Hyperinsulinemia associated with obesity inhibits secreted levels of sex hormone-binding globulin, further contributing to elevated levels of estrogen [11]. Notwithstanding the low risk of estrogen-alone HRT, elevated estrogen levels are associated with the elevated breast cancer risk observed in postmenopausal obese women [11]. We recently demonstrated that progestins can induce inflammatory processes in the mammary gland, recruiting leukocytes to sites adjacent to the mammary epithelium [17]. Several studies have shown that inflammation contributes to tumor growth and metastasis [18]. This may be one factor that explains the breast cancer risk associated with progestin-containing HRT. Given the implications for estrogen and progesterone in breast cancer development, studies are needed to assess dietary influences on hormonal levels, particularly during puberty given the association of early puberty with increased breast cancer risk.

Much focus has been placed on adult obesity as a low-grade inflammatory condition and diets abundant in saturated fat have been reported to directly induce inflammation through the activation of Toll-like receptor signaling in murine adipocytes and macrophages [19], leading to NF-κB and JNK activation with subsequent cytokine production. Palmitate, a major component of animal fat in the western HFD has been implicated particularly in these effects [20]. A HFD can also acutely induce low-grade inflammation after feeding [21]. This may occur through increased permeability of the gut, allowing increased levels of bacterial endotoxins to enter the circulation [22]. There is significant evidence at the molecular level that many cancers, including breast cancer, are linked to a dysregulated inflammatory response. Epidemiological studies also indicate that anti-inflammatory drugs reduce the risk of both receptor-positive and -negative breast cancer [23]. Animal models of breast cancer have demonstrated that inflammatory processes contribute to tumor proliferation and metastasis [18]. Consistent with this, anti-inflammatory drugs have been used in animal models for chemoprevention of mammary cancer [24]. The association of a HFD with inflammation has clear implications for its possible impact on breast cancer risk.

Finally, the effects of HFD may be refracted through the genetic backgrounds of the affected individuals. Divergent effects of HFD are observed between the BALB/c and C57BL/6 strains of mice [25]. While HFD induces the proliferation and development of mammary glands in BALB/c mice in the absence of obesity, a HFD causes obesity and actually stunts mammary gland development in C57BL/6 mice. While the underlying basis of these strain-specific differences is not known, the genetic variability of human populations suggest that the effects of a HFD may vary between individuals.

As stated previously, increased prepubertal BMI is highly associated with early pubertal maturation and the onset of menses – known risk factors for breast cancer. While the underlying mechanisms are not completely understood, the western diet, high in saturated fat and largely credited for the obesity epidemic in the USA, is suspected to be causal. Given the associations of a HFD with both increased breast cancer risk and inflammation, and the association of inflammation with cancer, further research is clearly needed to define these processes in children because of their potential significance for the predisposition to chronic diseases and breast cancer, in particular.