Breast cancer is the most common cancer in women and is a serious global health problem. The growth of approximately 70% of breast cancers depends on estrogen (17beta-estradiol or E2) and estrogen receptor (ER) signaling, with estrogen receptor A (ER-alpha) playing a more important role in progression of cancer compared to the beta isoform (ER-beta). ERs regulate gene expression in two ways: through direct DNA binding to estrogen-responsive elements (EREs) in the regulatory regions of their target genes, or through protein-protein interactions with other transcription factors, such as the aromatic hydrocarbons receptor (AhR). This is a ligand-dependent nuclear factor and a member of the PAS/ARNT family of transcription factors that mediate the toxicity of environmental contaminants, such as TCDD (dioxin), but binds many other endogenous, food, and drug compounds.
Upon ligand binding, the AhR translocates to the nucleus, heterodimerizes with ARNTs, and binds to specific DNA response elements (AHREs). Many research groups in the past have reported mutual crosstalk between AhR and ER-alpha. Activated AhR inhibits many ER-dependent responses; for this reason, AhR agonists have been suggested as potential therapeutic targets for ER+ breast cancer. In support of this, patients with AhR-positive breast cancer have a relatively better prognosis than those with AhR-negative tumors. However, ER-alpha-dependent modulation of AhR-regulated transcription is less clear; and has been reported to range from activation, to inhibition, to no effect. These differential findings may be due to the cellular context and specific responses examined.
However, both ER and AhR are activated/inhibited by numerous compounds including a wide range of food plant substances, such as resveratrol (RES) and 3,3-diindolyl-methane (DIM). The former is present in grapes, wine and dried fruit, while the latter is present in broccoli, cauliflower, cabbage and similar vegetables. RES is an AhR antagonist and inhibits AhR-dependent transcription; RES is also a phytoestrogen and activates ER signaling, although there are some studies reporting that it inhibits ER-alpha. The ability of the RES to do this may be, in part, due to its ability to inhibit aromatase activity. There is also evidence that DIM has both estrogenic and antiestrogenic effects, some of which are mediated by the AhR. In some studies, it can also activate ER-alpha and stimulates the expression of estrogen-responsive genes that require the help of protein kinase A (PKA).
However, although AhR and ER-alpha have many common points of regulation and target genes, when cells are exposed to DIM or RES the involvement of nuclear proteins is largely different. The scientists found that co-occupied sites after both DIM and E2+TCDD enrichment for AHREs included the neuronal transcription factor NPAS4, AP-2 gamma, and hypoxia-inducible transcription factor beta 1 (HIF-1B). In contrast, transcription factor motifs uniquely enriched among sites co-occupied by DIM included the transcription factor TCFCP2L1, TGFB-induced homeobox factor 1 (TGIF1); the GATA 3 protein, the nuclear receptor NR4A1 (or Nur77; also involved in breast cancer); among the unique motifs of E2+TCDD were forkhead box K2 (FOXK2), Neurofibromin 1 (NF1) and the cellular receptor PPAR-alpha.
Compared to TCDD alone, DIM resulted in greater genome-wide AhR binding and differentially expressed genes that were also associated with an AHRE. This information suggests that this is due to the ability of DIM to activate both ER-alpha and AhR. This is supported by the observation that AhR binds to additional genomic sequences after DIM or E2+dioxin treatment compared to dioxin alone. This suggests that when both ER-alpha and AhR are activated, ER-alpha recruits AhR to its target genes. In support of this, the scientists found that 96% of the genes bound by AhR after E2+TCDD were also bound by AhR after addition of DIM. In both treatments, an ERE site was the most enriched motif followed by an AHRE. All this information opens up interesting options for preventive therapy.
Both DIM and RES are chemopreventive substances for tumors. The consumption of vegetables such as broccoli, various types of cauliflower, Brussels sprouts and the like is recommended by the scientific community for the prevention of breast, uterine, colon and even prostate cancer. Their active ingredients sulforaphane and indole-3-carbinol are considered the main substances capable of this effect. Indole-3-carbinol is then converted during digestion to DIM and it is likely that foods and exogenous compounds mediate their actions through multiple signaling cascades, rather than a single cellular target. RES, however, is not just an estrogen agonist/antagonist; it inhibits protein-tyrosine kinases (c-Fyn, c-Src, the EGF receptor, to name a few) but is above all a natural activator of sirtuin (SIRT-1), a cellular mediator that controls the aging process.
Therefore, the view that real tumor chemoprevention is not achieved by focusing on a single active food ingredient is gaining ground. To give an example of breast cancer, it is not only the consumption of cruciferous vegetables (cauliflowers and the like) that prevents it; the active ingredients of the latter have specific molecular targets. But consume berries (with their anthocyanins and resveratrol), fruits rich in vitamin C (which takes oxidative stress out of the equation), soy-based foods (with its isoflavones that can antagonize some effects of estrogen) and vegetables dark in color (which is rich in quercitin, a flavonoid that is antioxidant and inhibits multiple cellular proteins), can help work with the active ingredients of Cruciferous vegetables, targeting additional targets that work together to achieve malignant cellular transformation.
Therefore, the view that real tumor chemoprevention is not achieved by focusing on a single active food ingredient is gaining ground. To give an example of breast cancer, it is not only the consumption of cruciferous vegetables (cauliflowers and the like) that prevents it; the active ingredients of the latter have specific molecular targets. But consume berries (with their anthocyanins and resveratrol), fruits rich in vitamin C (which takes oxidative stress out of the equation), soy-based foods (with its isoflavones that can antagonize some effects of estrogens) and vegetables dark in color (which is rich in quercitin, a flavonoid that is antioxidant and inhibits multiple cellular proteins), can help work with the active ingredients of Cruciferous vegetables, targeting additional targets that work together to achieve malignant cellular transformation.
Therefore, the real chemoprevention should be achieved with several sustances of different nature, because each of them has preferential targets often not shared, that could work synergistically to effectively avoid carcinogenesis.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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