Redefining the impact of nutrition on breast cancer incidence: is epigenetics involved?

Abstract

Breast cancer incidence is rising worldwide with an increase in aggressive neoplasias in young women. Possible factors involved include lifestyle changes, notably diet that is known to make an impact on gene transcription. However, among dietary factors, there is sufficient support for only greater body weight and alcohol consumption whereas numerous studies revealing an impact of specific diets and nutrients on breast cancer risk show conflicting results. Also, little information is available from middle- and low-income countries. The diversity of gene expression profiles found in breast cancers indicates that transcription control is critical for the outcome of the disease. This suggests the need for studies on nutrients that affect epigenetic mechanisms of transcription, such as DNA methylation and post-translational modifications of histones. In the present review, a new examination of the relationship between diet and breast cancer based on transcription control is proposed in light of epidemiological, animal and clinical studies. The mechanisms underlying the impact of diets on breast cancer development and factors that impede reaching clear conclusions are discussed. Understanding the interaction between nutrition and epigenetics (gene expression control via chromatin structure) is critical in light of the influence of diet during early stages of mammary gland development on breast cancer risk, suggesting a persistent effect on gene expression as shown by the influence of certain nutrients on DNA methylation. Successful development of breast cancer prevention strategies will require appropriate models, identification of biological markers for rapid assessment of preventive interventions, and coordinated worldwide research to discern the effects of diet.

Fig. 1

Epigenetic mechanisms of gene transcription. An average of 147 bp of double-stranded DNA (black thick line) are wrapped around histone octamers to form nucleosomes. Two sets of four distinct histones (3, 4, 2B and 2A) form the octamer. The loosening of DNA is obtained by triggering of histone modifications (for example, acetylation on lysine 12 of histone 4 and trimethylation on lysine 4 of histone 3) that leads to a decrease in the tightness of interactions among histones and between histones and DNA and, thus, an open chromatin stage amenable for transcription. Other histone modifications (for example, trimethylation of histone 3 on lysine 27 or on lysine 9) are conducive to gene silencing by compacting nucleosomes tightly. In certain gene promoters a stretch of DNA of several hundred bp enriched in C-phosphate-G (CpG) islands could become methylated. This chemical modification has been considered as one of the sustainable changes leading to epigenetic inheritance through cell division and is found in a number of tumour-suppressor genes when cancer develops. Note: histone octamers are shown as blocks of eight light grey barrels, each barrel representing an individual histone. This is a simplified representation of chromatin organisation. The complex orientation of histones within the octamer and the histone 1 linker are not shown; the multiple protein complexes that are necessary to chemically modify histones and DNA (for example, with methylases, histone deacetylases) as well as those involved in histone displacement (for example, chromatin remodelling complexes) are not drawn.

Fig. 2

Possible impact of epigenetic modifications upon dietary influence during the lifespan of the mammary gland. There is still much to be understood regarding human breast development and a lot of information is extrapolated from studies in rodents. The human mammary gland evolves constantly with the formation, on average, of twelve individual ductal systems or lobes with limited branching of ducts with blunt-ended ductal termini during fetal development. Considerable secondary branching and elongation of the ductal systems and formation of terminal ductal lobular units (TDLU) occur upon hormonal stimulation during puberty, and lobes further branch out to develop into lactating tissue followed by involution of part of the glandular tissue during pregnancy/lactation cycles. All the phases of development will encompass TDLU (these structures are present in the majority starting at puberty and until menopause), thus affecting areas of the breast where cancers develop. Therefore, epigenetic alterations occurring at different periods during the lifespan of an individual might affect the mammary gland to various extents based on the possibility to propagate permanent/long-term epigenetic marks through cell division (see grey arrows). The period between birth and puberty is not accompanied by extensive breast development; instead, it is proposed to comprise an involution phase shortly after birth and slow growth that accompanies the body’s growth afterwards; this period is represented by the dashed line on the drawing (periods of times between life events are not represented to scale). Menopause is characterised by a reduction in the number of TDLU and ducts⁽²⁸⁰⁾.

Fig. 3

Venn diagram of a relationship between diets/food components and factors that influence their impact on breast cancer risk. Major life characteristics share specific relationships with diets/food components when it comes to breast cancer. These characteristics include the stage of mammary gland development (which encompasses menopausal status/age) and the individual’s background (race/ethnicity and lifestyle other than dietary habits). The combination of these different factors might explain why certain nutrients will have an impact on the development of a certain type of breast tumour. Such knowledge is critical for optimal primary prevention, as it suggests that (1) the study of the impact of diets/food components on breast cancer has to take into account diversity and (2) the link between the development of a certain type of breast tumour and nutrition has to be further scrutinised, notably via the identification of the early alterations in the breast specific to a given type of neoplasia. ER +, oestrogen-positive; ER−, oestrogen-negative; PR +, progesterone-positive; PR−, progesterone-negative.