Breast cancer is the most common cancer and the leading cause of cancer death in women worldwide. It is not considered a single disease but a heterogeneous group of several diseases of distinct molecular subtypes. Breast cancer can be classified into four subtypes, luminal A, luminal B, basal and HER2-positive. Although the overall mortality rate for breast cancer patients has decreased in developed countries, patients diagnosed with the baseline subtype have a poorer short-term prognosis than those diagnosed with other breast cancer subtypes. About one sixth of breast cancer cases are classified as triple negative breast cancer (TNBC), named after the absence of estrogen receptor (ER), progesterone receptor (PRa) and human epidermal growth factore receptor (EGRF or HER2) expression.
Most cases of basal-type breast cancer are also referred to as TNBC because it is characterized by the lack of expression of these three biomarkers. Soy products have long been suggested to be useful in the prevention of cancer development. Epidemiological studies have shown the preventive effect of soy intake for breast cancer. In particular, Asian women who consume a diet rich in soy products have a lower incidence of breast cancer and a lower risk of breast cancer recurrence than women in western counties. Genistein, a phytoestrogen, is the main isoflavonoid contained in soybeans and is considered the active micronutrient responsible for its chemopreventive effect. Things are a little different in the case of the intake of soy or soy-based foods in the context of patients who have breast cancer.
Genistein is an isoflavone that was originally found to be an estrogen receptor agonist (ER-alpha), although later and more recent studies have shown that it urges preference for the beta isoform (ER-beta), which is not directly implicated in the proliferation of normal or malignant breast cells. Indeed, the results of in vitro mechanistic studies show that the antitumor activity of genistein in breast cancer cells is largely attributable to the preferential induction of ERβ, which suppresses ERα signaling. Given the possibility, however, that genistein behaves as an aromatic compound capable of activating the ER-alpha receptor, oncologists and endocrinologists advise against taking soy and its derivatives in case of classic breast cancer that expresses receptors for estradiol and / or progesterone.
This may be different in the case of triple-negative tumors. This isoflavone has a broad spectrum of anticancer properties in triple negative breast cancer cells. Genistein can inhibit cell growth, induce G2/M phase arrest and/or apoptosis, and decrease cell invasiveness in TNBC cells. This happens as genistein can enhance the expression of stop proteins (p53, p21WAF) while repressing cell death protectors such as Bcl-2 and the transcription factor NF-kB. Overall, it is known that genistein can inhibit some tyrosine kinases such as c-Src and the EGF receptor and can interfere with nuclear enzymes, such as topoisomerase I (Top-1) and DNA-methyltransferase (DNMT-1). There is some evidence that it might interfere as well with MEK-1, a protein kinase component of the MAP kinase signaling pathway.
More recent analyzes based on phospho-proteomics and bioinformatics have shown that genistein can modulate phosphorylation on proteins involved in cell cycle regulation and DNA damage response. They include critical components of the DNA replication fork, the cohesion complex, kinetochores and the BRCA1 complex. A particular regulation in triple-negative tumor cells was recorded in proteins such as histone H2.1, cyclin B1, thymidine kinase and few others. The vast majority of cellular proteins, therefore, do not appear to be conditioned in their expression in the context of triple-negative malignant cells. What seems to change, however, is their secondary modification state or phosphorylative state: nearly a hundred proteins undergo this variation when cultured MDA-MB-231 (triple-negative) cells are treated with genistein.
Of these, more than 20 are involved in the cellular response to radiation-induced genomic damage (such as ATR, BACH-1, ATRIP, TOPBP1, RAP80 and also the famous tumor suppressor BRCA-1). These responses are not late (24h or more), but occur after just 3 hours, indicating that genistein affects transduction pathways made of protein kinase. Other cellular responses, on the other hand, could depend on the involvement of longer genetic responses. The tumor suppressor BRCA-1 seems to be present in triple-negative malignant cells, but the genetic and epigenetic variations seem to keep it in a silent state that prevents it from acting on cellular malignancy. Genistein seems to restore its expression through the activation of a pathway sensitive to aromatic compounds, that of the hydrocarbon receptor or AhR, a transcription factor that can be activated or inhibited depending on what type of aromatic compound it manages to bind.
It is generally recognized that plant polyphenols and flavonoids block it, which leads to a tumor growth suppression effect and therefore to a chemopreventive effect. The genetic activity of BRCA-1 is also essential for the ER-alpha receptor to be expressed, which gives cancer cells sensitivity to estrogen or, even better, to anti-estrogens used in breast cancer chemotherapy. In fact, a very recent study has shown that TNBC cells treated with genistein show alterations of the epigenome (methylation state) in the BRCA-1 gene. In this case, from hyper-methylated the gene becomes hypomethylated and resumes its expression.It is curious that when the AhR receptor is bound to aromatic compounds, it also drags with it the DNMT1 enzyme for DNA methylation on the promoter of the BRCA-1 gene, which coincidentally is also inhibited by genistein itself.
This process allows the function of BRCA-1 and the subsequent expression of the ER-alpha receptor. In this way, the triple-negative cells become sensitive again to tamoxifen, one of the historical antiestrogens used against breast cancer. The study showed that the effect of genistein appears not only in cultured cell models, but also in laboratory mice to which genistein has been added to the diet. Scientists deem that in the case of triple-negative breast cancers, genistein supplementation or introduction of soy in the diet, might help manage cancer status, enhancing the possibility to restore its sensibility to drugs of the antiestrogens group.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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