Specific transcriptional response of four blockers of estrogen receptors on estradiol-modulated genes in the mouse mammary gland

Abstract

Novel agents for the endocrine therapy of breast cancer are needed, especially in order to take advantage of the multiple consecutive responses observed in metastatic progressing breast cancer following previous hormone therapy, thus delaying the use of cytotoxic chemotherapy with its frequent poor tolerance and serious side effects. Acolbifene (ACOL) is a novel and unique antiestrogen which represents a unique opportunity to achieve the most potent and specific blockade of estrogen action in the mammary gland and uterus while exerting estrogen-like beneficial effects in other tissues, especially the bones. To better understand the specificity of action of ACOL, we have used Affymetrix GeneChips containing 45,000 probe sets to analyze 34,000 genes to determine the specificity of this compound compared to the pure antiestrogen fulvestrant, as well as to the mixed antagonists/agonists tamoxifen and raloxifene to block the effect of estradiol (E(2)) and to induce effects of their own on the genomic profile in the mouse mammary gland. The genes modulated by E(2) were those identified in two separate experiments and validated by quantitative real-time PCR (qPCR). Three hours after the single subcutaneous injection of E(2) (0.05 μg), the simultaneous administration of ACOL, fulvestrant, tamoxifen, and raloxifene blocked by 98, 61, 43, and 92 % the number of E(2)-upregulated genes, respectively. On the other hand, 70, 10, 25, and 55 % of the genes down-regulated by E(2) were blocked by the same compounds. Of the 128 genes modulated by E(2), 49 are associated with tumorigenesis while 22 are known to be associated with breast cancer. When used alone, ACOL modulated the smallest number of genes also influenced by E(2), namely 4 %, thus possibly explaining potential utilities of this compound in breast cancer prevention and therapy.

Effects of Pubertal Exposure to Dietary Soy on Estrogen Receptor Activity in the Breast of Cynomolgus Macaques

“…This finding is consistent with the large increase of lobuloalveolar differentiation found in these animals (18), suggesting a soy promotional effect on breast differentiation through menarche. There was also a trend of lower GATA-3 with soy following menarche, which was consistent with the pattern of ERα and GREB1 mRNA and a study in ovariectomized mice that showed downregulation of GATA-3 expression through ER modulation induced by exogenous estrogen (49). …”

Transforming growth factor beta1 targets estrogen receptor signaling in bronchial epithelial cells

“…RBP7 has been shown to be up-regulated in IPF lung tissue [71] and in wound tissue in the normal chicken chorioallantoic wound model [72] although its role in fibrosis is unclear. RBP7 is positively regulated by E2 in breast cancer cells [73] and mouse mammary gland [74]. The discrepancy in regulation in our study may be a result of variable exposure dynamics as the study by Calvo et al exposed mice to one dose of E2 and sacrificed the animals 3 h later [74] while we exposed cells in vitro for 24 h. Nonetheless, E2 appears to regulate RBP7 which may exhibit an unexplored effect on fibrogenic signaling.…”

Clinical Trial of Acolbifene in Premenopausal Women at High Risk for Breast Cancer

“…There was no clear effect on the chemokine stromal cell-derived factor 1 (SDF-1) which is important for viability of stem cells and has been implicated in ligand-independent phosphorylation of the estrogen receptor and tamoxifen resistance [37–39] Tamoxifen has been variably associated with increases in SDF-1 [34, 40, 41]. A recent report assessing the short term effects of several SERMs and fulvestrant on a large number of genes in mammary cancer from ovariectomized mice suggests that acolbifene reverses the effect of estradiol on more estrogen inducible genes than tamoxifen, raloxifene, or fulvestrant [42]. …”