Volume 9, Issue 1

No abstract available

Reduction in breast cancer risk is associated with elevated circulating levels of human chorionic gonadotropin (hCG) during the first trimester of gestation. The knowledge that hCG also modifies the genomic signature of breast epithelial cells, from highly susceptible to refractory, to undergo neoplastic transformation, and also exerts both preventive and therapeutic effects on chemically induced mammary cancer, lead us to select this hormone for inducing chromatin remodeling in breast epithelial cells as a surrogate end point of complete differentiation and cancer prevention. We have found that chromatin remodeling is the driving force of the differences between the nulliparous and parous breast. In the parous breast, the epithelial cells have a condensed chromatin and increased reactivity with anti-H3K9me 2 [di-methyl histone 3 (H3) (Lysine 9)] and H3K27me 3 antibodies. This is accompanied by upregulation of noncoding RNA (ncRNA) elements including X 2 -inactive specific transcript (XIST) and chromatin remodeling genes, such as chromodomain helicase DNA-binding protein 2 ( CHD2 ) and the chromobox homolog 3 ( CBX3 ), whose products are required for controlling recruitment of protein/protein or DNA/protein interactions Another important gene upregulated in the parous breast epithelial cells is the histone-lysine N-methyltransferase or enhancer of zeste homolog 2 ( EZH2 ), a member of the polycomb group (PcG) forming multimeric protein complexes that maintains the transcriptional repressive state of genes over successive cell generations. The fact that recent studies indicate that ncRNAs recruit PcG complexes to the locus of transcription or to sites located elsewhere in the genome cause us to postulate that the increased chromatin condensation in the parous breast has been initiated by ncRNAs, a postulate supported by the observed upregulation of several ncRNAs that included the XIST . The identification of a specific genomic signature of pregnancy has uncovered a novel tool that will serve as a surrogate biomarker for testing new chemopreventive agents and will significantly advance the field of cancer prevention. The clinical impact of this work is that it validates in an experimental system the genomic signature of prevention identified in the human parous breast and establish the bases for the use of the hormone hCG in the prevention of breast cancer, an approach that has not been fully developed until now.

Pregnancy can both reduce and increase lifetime breast cancer risk, and it also induces a short-term, transient increase in risk. Several biological mechanisms have been proposed to explain the protective effect, including pregnancy-induced increase in circulating estrogen levels leading to reduced estrogen receptor (ER) expression and activity. Persistent changes in ER-regulated gene expression may then alter the response of the breast to postpregnancy hormonal exposures originating, for example, from food. Understanding how pregnancy increases breast cancer risk has received less attention. Human studies indicate that those women who were exposed to an elevated pregnancy estrogenic environment, such as women who took the synthetic estrogen diethylstilbestrol or who had the highest circulating estrogen levels at the beginning or end of pregnancy, are at increased risk of developing breast cancer. There is also evidence that elevated leptin levels, for example, in pregnant women who gained excessive amount of weight, increase later breast cancer risk. This may reflect a close interaction between estradiol (E2), ER, and leptin. Our preclinical study suggests that an exposure to excess pregnancy E2 and leptin levels reverses the protective changes in genomic signaling pathways seen in the breast/mammary gland of parous women and rodents. Recent findings indicate that involution – the period after lactation when the breast regresses back to prepregnancy stage – may be related to some pregnancy-associated breast cancers. Importantly, in a preclinical model, the increase can be reversed by anti-inflammatory treatment, offering hope that the increase in lifelong breast cancer risk induced by late first pregnancy or by an exposure of pregnant women to an excessive hormonal environment may be reversible.

The bioformation and transformation of estrogens and other hormones in the breast tissue as a result of the activity of the various enzymes involved attract particular attention for the role they play in the development and pathogenesis of hormone-dependent breast cancer. The enzymatic process concerns the aromatase, which transforms androgens into estrogens; the sulfatase, which hydrolyzes the biologically inactive sulfates to the active hormone; the 17β-hydroxysteroid dehydrogenases, which are involved in the interconversion estradiol/estrone or testosterone/androstenedione; hydroxylases, which transform estrogens into mitotic and antimitotic derivatives; and sulfotransferases and glucuronidases, which, respectively convert into the biologically inactive sulfates and glucuronides. These enzymatic activities are more intense in the carcinoma than in the normal tissue. Concerning aromatase, the application of antiaromatase agents has been largely developed in the treatment of breast cancer patients, with very positive results. Various studies have shown that the activity levels of these enzymes and their mRNA can be involved as interesting prognostic factors for breast cancer. In conclusion, the application of new antienzymatic molecules can open attractive perspectives in the treatment of hormone-dependent breast cancer.

Growth responses to oestrogen can be reproducibly obtained using a selection of oestrogen-receptor-containing human breast cancer cell lines, and molecular mechanisms have been shown to include modulation to growth factor/receptor/signalling pathways, cell-cycle proteins, apoptosis, differentiation, adhesion, motility and migration. Considerable progress has been made in understanding the molecular basis of oestrogen action on gene expression through the ligand-activated transcription factors human oestrogen receptor α (ERα) and ERβ and the resulting effects on global gene expression patterns, but the full profile of coordination of the alterations, which brings about changes in cell growth through genomic and non-genomic mechanisms remain to be fully elucidated. Oestrogen regulation of cell growth involves a complex cross-talk between oestrogen receptor and growth factor signalling pathways such that inhibition of one pathway may lead to stimulation of another, which may explain the remarkable ability of human breast cancer cells to escape from any mode of imposed growth inhibition be it oestrogen deprivation or administration of antioestrogen. Although studies on cell growth have focused to date on the effects of physiological oestrogens, many hundreds of environmental chemicals with oestrogenic properties have now been measured in the human breast. Whether or not the weight of evidence eventually establishes any causal link of complex mixtures of environmental oestrogenic chemicals with breast cancer, the presence of so many oestrogenic chemicals in the breast must influence resulting oestrogenic responses, and the impact of this additional oestrogenic burden needs to be taken into account in future studies on growth regulation of human breast cancer cells.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that is clinically negative for the expression of estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2 (HER2). Patients with TNBC have a worse clinical outcome, as measured by time to metastasis and median overall survival. Chemotherapy has been the mainstay of treatment of TNBC but responses are disappointing. A substantial proportion of TNBC expresses luteinizing hormone-releasing hormone (LHRH), receptors for LHRH, in addition to receptors for growth hormone-releasing hormone (GHRH). These receptors represent potential therapeutic targets. Potent antagonists of GHRH and LHRH receptors have been developed in recent years and these antagonists inhibit the growth, tumorigenicity and metastatic potential of various human experimental malignancies. These antagonists could be utilized for the treatment of TNBC. The targeted cytotoxic analog of LHRH, AN-152 (AEZS-108) containing doxorubicin, must also be strongly considered for therapy of TNBC. Experimental studies suggest the merit of clinical trials with LHRH antagonists and AEZS-108 in TNBC patients.

Background: Estetrol (E4) is a pregnancy-specific estrogenic steroid hormone produced by the human fetal liver in both male and female fetuses. During pregnancy, E4 plasma values increase exponentially until parturition and decrease thereafter. The synthesis of E4 in the liver of a newborn ceases during the first weeks after birth. Materials and methods: Here we report the effect of E4 on the initiation and growth of mammary tumors chemically induced by 7,12 dimethylbenz(a)anthracene (DMBA) in female Sprague-Dawley rats in two different protocols. Two prevention studies to test the effect on initiation and growth of induced tumors and one intervention study to test the effect on tumor growth were performed. In the prevention studies, the effect of oral doses of E4 over a dose range of 0.5–3.0 mg/kg was investigated. In the intervention study, oral doses of 1, 3 and 10 mg/kg E4 were used. The anti-estrogen tamoxifen (TAM) and ethinylestradiol (EE) were used as reference compounds. In all studies, a group with ovariectomized animals (OVX) was included. Results: In the prevention studies, 2.5 mg and 3 mg/kg E4 showed a significant effect on the number and growth of induced tumors by DMBA, and the effects were comparable to those of TAM, whereas EE had no effect. In the intervention study, the effect of a high dose of E4 (10 mg/kg) on tumor number was similar to that of OVX and better than TAM and high-dose EE. The 3 mg/kg E4 had an effect comparable to high-dose EE. The treatment effects were largely due to complete regression of existing tumors. Conclusions: The natural fetal estrogen E4 prevents tumor initiation by DMBA and inhibits the growth of existing DMBA-induced tumors.