Breast Cancer

Author: Daniela Attianese
Date: 18/01/2012




About 5% of all cases of breast cancer occurs in carriers of high-penetrance mutations of genes that predispose to the development of this tumor, two of which have been identified and cloned (BRCA1 and 2) . Over 50% of carriers become ill, but several studies have suggested that their risk may be modulated by environmental and nutritional factors can interact with the functions of the BRCA genes themselves, ranging from DNA repair processes to hormonal regulation.

Biochemical, genetic and cytological studies have revealed multiple functions for BRCA1 and BRCA2.
Many of the proteins with which BRCA1 and BRCA2 interact have been identified. BRCA1 and BRCA2 proteins are involved in control of homologous recombination (HR) and double-strand break repair in response to DNA damage. A role for BRCA1 in the early cellular response to DNA damage has been described.
BRCA1 and BRCA2 also function as transcriptional co-regulators through direct interaction with sequence-specific transcription factors and with components of the transcriptional machinery.
Cells that lack BRCA1 or BRCA2 accumulate chromosomal abnormalities including chromosomal breaks, severe aneuploidy and centrosome amplification. Chromosomal instability as a result of BRCA1 or BRCA2 deficiency may be the pathogenic basis for breast tumor formation.

BRCA1 and BRCA2 and the genetics of breast and ovarian cancer
Hum. Mol. Genet. (2001) 10 (7): 705-713.
Oxford Journal

ROLE OF DIET IN BREST CANCER’S RISK: vegetables from cruciferous

The study "COS" evaluated the interaction between genetic susceptibility and nutritional factors.
The consumption of vegetables from the cruciferous family has emerged as an important protective factor for BRCA mutation carriers. It is hypothesized that this protection is due to the high content of cruciferous indole-3carbinolo, which reduces the activity of estrogens favoring the hydroxylation at C-2 rather than C-16. Previous studies have suggested that 2-hydroxyestrone is protective against breast cancer, whereas the other principal metabolite, 16 alpha-hydroxyestrone, and the lesser metabolite quantitatively, 4-hydroxyestrone, are potent carcinogens.

IARC Sci Publ. 2002;156:63-5
A European case-only study on familial breast cancer.
Berrino F, Pasanisi P, Berrino J, Curtosi P, Bellati C. Epidemiology Unit, National Cancer Institute, Milan, Italy.
Pub Med

Implicated mechanism

Indole-3-carbinol, a compound found in cruciferous vegetables, has been shown that it induces CyP4501A1, increasing 2-hydroxylation of estrogens, leading to the protective 2-OHE1, and also decreases CyP1B1 sharply, inhibiting 4-hydroxylation of estradiol, thereby decreasing the formation of the carcinogenic 4-OHE1.

Multifunctional Aspects of the Action of Indole-3-Carbinol as an Antitumor Agent
Article first published online: 6 FEB 2006
Wiley On Line Library

The metabolism of estrone and estradiol occurs through different pathways, including the 2-, 4-, and 16α-hydroxylation pathways and experimental studies have shown that estrogen metabolites may have differential estrogenic and genotoxic activities. For example, the metabolites in the 4- and 16α-hydroxylation pathways may have higher estrogenic activity than estradiol while 2-catechol estrogen metabolites may act as either weak mitogens or inhibitors of proliferation.
Thus, the specific pattern of estrogen metabolism has been hypothesized to influence a woman’s breast cancer risk, either through estrogen receptor-mediated cell proliferation or through genotoxic effects of the metabolites.

J Steroid Biochem. 1989 Apr;32(4):485-92
Binding of 2-hydroxyestradiol and 4-hydroxyestradiol to estrogen receptors from human breast cancers.
Van Aswegen CH, Purdy RH, Wittliff JL.
Pub Med


High consumption of brassicaceous vegetables, including broccoli, has other important role in cancer prevention. Cancer prevention is hypothesised to act through various mechanisms including modulation of xenobiotic metabolising enzymes, NF-E2 p45-related factor-2 (Nrf2)-mediated stress-response mechanisms, and protection against genomic instability.
Infacts cells can survive chronic oxidative stress by enhancing activities of antioxidant enzymes, thereby protecting cells from deoxyribonucleic acid (DNA) damage. In common with many other ITCs, SF raises tissue glutathione (GSH) levels by stimulating the antioxidant-response elements (ARE) in the 50-upstream region of the gene for the heavy sub-unit of gglutamylcysteine synthetase. This enzyme catalyses the rate-limiting step in glutathione synthesis. The genes encoding NF-E2 p45-related factor-2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) play an important role in the induction of antioxidant enzymes against oxidative stress. Nrf2 is a major transcription factor involved in regulating antioxidant and pro-inflammatory genes.

2012 Jan;56(1):126-46.Epub 2011 Dec 7.
The potential role of nutritional genomics tools in validating high health foods for cancer control: broccoli as example.
Ferguson LR, Schlothauer RC.
Pub Med


Cow's milk is rather emerged as an important risk factor. It is assumed that the risk of milk depends on the stimulus that this food has on the synthesis of insulin-like growth factor type 1 (IGF-I). Studies suggest that serum levels of IGF-I are related to an higher risk to develop breast cancer in women with BRCA mutation.
Insulin-like growth factor 1 (IGF1) is a peptide which stimulates mitosis and inhibits apoptosis. Around 99% of IGF1 circulates bound to IGF binding proteins, with most bound to IGF binding protein 3 (IGFBP3) in a ternary complex with an acid labile subunit. Less than 1% of IGF1 circulates unbound. Most prospective studies of IGF1 and breast-cancer risk have also reported on IGFBP3, to explore the hypothesis that women with a high concentration of IGF1 relative to IGFBP3 are at an increased risk of breast cancer.

Lancet Oncol. 2010 June; 11(6): 530–542.
Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies
The Endogenous Hormones and Breast Cancer Collaborative Group
Pub Med

Also estrogens are important in the etiology of breast cancer, and there is laboratory evidence for crosstalk in cells between the signalling pathways for estrogens and IGF1. Estradiol enhances IGF-1R signalling by inducing the expression of insulin receptor substrate 1 (IRS-1), a substrate of the IGF-1R. Estradiol induced expression of IRS-1 results in enhanced tyrosine phosphorylation of IRS-1 after IGF-1 stimulation, followed by enhanced mitogen activated protein kinase, phosphoinositide 3′ kinase, and Akt activation.

Insulin-like growth factor 1 and oestradiol promote cell proliferation of MCF-7 breast cancer cells: new insights into their synergistic effects
J Dupont and D Le Roith
Pub Med

Role of zinc

Restricted intakes of energy, protein, and zinc in animals and children are associated with reduced concentrations of serum IGF-I and reduced growth, both of which are improved with nutritional repletion and in cases of zinc deficiency, zinc supplementation. Recent investigation suggests that the effects of zinc deprivation on IGF-I concentrations may be independent of protein and energy intake. Reductions in energy and zinc intakes lead to reduced concentrations of serum IGF-I, growth hormone receptors, and growth hormone binding proteins.
The mechanism responsible for reduced serum IGF-I in zinc deficiency is associated with decreased hepatic IGF-I gene expression and defects in the intracellular growth hormone–signaling pathway that are restored by supplemental zinc.
Zinc deficiency per se affects the stability of the 7.5-kilobase IGF-I mRNA transcript and may affect the abundance, binding affinity, and stability of the protein.
The majority of circulating IGF-I (75–80%) is bound to the most abundant serum IGF binding protein, IGFBP-3. In states of protein deficiency, the preferential binding of IGF-I to the 150-kD circulating complex composed of IGFBP-3 and an acid-labile subunit is reduced and IGF-I subsequently binds to smaller-molecular-weight IGFBPs. These smaller proteins can pass through capillaries, leading to reduced circulating concentrations of IGF-I. This suggests that protein and zinc deficiency may also play a role in the stability of the IGFBPs and the clearance of IGF-I from the serum.
The major source of zinc consumed by most individuals is animal products (51%), namely, meat cereals and milk products.

Cancer Epidemiol Biomarkers Prev. 2002 Sep;11(9):852-61.
Dietary correlates of plasma insulin-like growth factor I and insulin-like growth factor binding protein 3 concentrations.
Holmes MD, Pollak MN, Willett WC, Hankinson SE
Pub Med

Am J Clin Nutr July 1998 vol. 68 no. 1 200-206
Effects of zinc and other nutritional factors on insulin-like growth factor I and insulin-like growth factor binding proteins in postmenopausal women1–3
Amanda Devine, Clifford Rosen, S Mohan, David Baylink, and Richard L Prince
The American Journal of Clinical Nutrition


Studies shows that a change on diet that includes the abolition of milk consumption and the introduction of a moderate consumption of cruciferous vegetables, may lower plasma levels of sex hormones and growth factors and then the incidence of breast cancer in women with a strong genetic predisposition.

Daniela Attianese e Andrea Carosso

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