Effects of Soy-Derived Isoflavones and a High-Fat Diet on Spontaneous Mammary Tumor Development in Tg.NK (MMTV/c-neu) Mice

Abstract

Phytoestrogens such as isoflavonoids and lignans have been postulated as breast cancer protective constituents in soy and whole-grain cereals. We investigated the ability of isoflavones (IFs) and flaxseed to modulate spontaneous mammary tumor development in female heterozygous Tg.NK (MMTV/c-neu) mice. Two different exposure protocols were applied, either from 4 wk of age onward (postweaning) or during gestation and lactation (perinatal). In the postweaning exposure study, mice were fed IFs or flaxseed in a high-fat diet. In addition, flaxseed in a low-fat diet was tested. Postweaning exposure to IFs and flaxseed tended to accelerate the onset of mammary adenocarcinoma development, although tumor burden at necropsy was not changed significantly. Perinatal IF exposure resulted in enhanced mammary gland differentiation, but palpable mammary tumor onset was not affected. However, tumor burden at necropsy in the perinatal exposure study was significantly increased in the medium- and high-IF dose groups. Comparison of both exposure scenarios revealed a strongly accelerated onset of tumor growth after perinatal high-fat diet exposure compared with the low-fat diet. This study shows that breast cancer-modulating effects of phytoestrogens are dependent both on the background diet and on the timing of exposure in the life cycle.

The role of early life genistein exposures in modifying breast cancer risk

“…Only one study in mice has investigated whether an exposure from conception until puberty to soy IFs (Luijten et al, 2004). This observation is opposite to the findings obtained in rats showing that an exposure from conception to weaning is protective against carcinogen-induced mammary tumours.…”

“…The findings obtained in these studies show that mice exposed to genistein during fetal development exhibit an increase in the number of TEBs as adults (reviewed by Warri et al, 2007). According to different studies, neonatal and/or pubertal genistein/ SPI exposure either increases (Luijten et al, 2004;Thomsen et al, 2005) or reduces (Yang et al, 2003) …”

“…The studies reported that the exposure reduced (Rao et al, 1997;Liu et al, 2005), increased (Thomsen et al, 2006), or had no effect (Day et al, 2001;Jin and MacDonald, 2002;Luijten et al, 2004) on mammary tumour incidence and/or multiplicity and size. In addition, a delayed tumour onset after genistein or soy exposure was reported in two of the six genetically modified mouse studies (Jin and MacDonald, 2002;Yang et al, 2003).…”

Maternal dietary exposure to fiber during pregnancy and mammary tumorigenesis among rat offspring

“…These findings are in line with previous observations suggesting that a mother's diet during pregnancy can modify a female offspring's later susceptibility to carcinogeninduced mammary tumorigenesis. 3,4,6,29,30 More broadly, breast cancer appears to be among the diseases that can have a fetal origin; the other diseases include hypertension, cardiovascular diseases, diabetes and mental disorders. 1 The fact that in utero exposure to whole wheat flour reduced later breast cancer risk extends other animal studies showing that wheat intake during adult life reduces tumor growth in the mammary gland.…”

“…For example, maternal exposure to a high fat diet during pregnancy increases a female offspring's susceptibility to develop carcinogen-induced mammary tumors in rats, 3,4 and mammary tumors in both outbred mice 5 and transgenic mice that overexpress c-neu oncogene. 6 Since in utero exposure to estradiol also increases mammary tumorigenesis 3 and a high fat diet increases pregnancy estradiol levels, 3,7 a high in utero estrogenic environment may be a key factor causing an increase in subsequent breast cancer risk. Consequently, a reduction in pregnancy estradiol levels may reduce offspring's susceptibility to develop mammary tumors.…”