Tumor Banks: A Quality Control Scheme Proposal.

Tumor banks make a considerable contribution to translational research. Using emerging molecular tests on frozen material facilitates the development of new diagnostic and therapeutic strategies, especially in rare cases. However, standard quality control schemes are lacking in the current literature.

SET: a robust 18-gene predictor for sensitivity to endocrine therapy for metastatic breast cancer.

There is a clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SET index to measure gene expression microarray probe sets that were correlated with hormone receptors ( and ) and robust to preanalytical and analytical influences. We tested SET index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients.

Distinctive Desmoplastic 3D Morphology Associated With BRAFV600E in Papillary Thyroid Cancers.

Context: Although 60% of papillary thyroid carcinomas are BRAFV600E mutant (PTCV600E), the increased aggressiveness of these cancers is still debated.

Objective: For PTCV600E we aimed to further characterize the extent of the stroma and its activation, the three-dimensional (3D) tumor-stroma interface, and the proliferation rates of tumor and stromal fibroblasts.

Design: We analyzed exomes, transcriptomes, and images of 364 papillary thyroid carcinoma (PTCs) from The Cancer Genome Atlas (TCGA), including 211 PTCV600E; stained 22 independent PTCs for BRAFV600E and Ki67; sequenced the exomes and stained BRAFV600E in 5 primary tumor blocks and 4 nodal metastases from one patient with PTCV600E; and reconstructed the 3D volumes of one tumor and one metastatic block at histological resolution.

ERα dimerization: a key factor for the weak estrogenic activity of an ERα modulator unable to compete with estradiol in binding assays.

Estrothiazine (ESTZ) is a weak estrogen sharing structural similarities with coumestrol. ESTZ failed to compete with [H]17β-estradiol ([H]17β-E) for binding to the estrogen receptor α (ERα), questioning its ability to interact with the receptor. However, detection by atomic force spectroscopy (AFS) of an ESTZ-induced ERα dimerization has eliminated any remaining doubts.

The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence.

Importance: The Genomic Grade Index (GGI) was previously developed, evaluated on frozen tissue, and shown to be prognostic in early breast cancer. To test the GGI in formalin-fixed, paraffin-embedded breast cancer tumors, a quantitative reverse transcriptase polymerase chain reaction assay was developed and named the Genomic Grade (GG). The GG assay has the potential to increase the clinical application of the GGI, but robust demonstration of the clinical validity of the GG assay is required.

Peptides targeting estrogen receptor alpha-potential applications for breast cancer treatment.

Activation of the estrogen receptor alpha (ERα) is of prime importance for the development of hormone-dependent breast cancers. Hence, drugs able to impede the emergence of an active folding of ERα have been used for a long time as a first line therapeutic strategy. Aromatase inhibitors that block estradiol synthesis and / or antiestrogens that compete with hormone binding to the receptor are routinely prescribed.

A ferrocenyl derivative of hydroxytamoxifen elicits an estrogen receptor-independent mechanism of action in breast cancer cell lines.

The aim of this work was to investigate the mechanism of action of ferrocifen (Fc-OH-TAM), the ferrocenyl analog of 4-hydroxy-tamoxifen (OH-TAM), which is the active metabolite of tamoxifen, the drug most widely prescribed for treatment of hormone-dependent breast cancers. Fc-OH-TAM showed an anti-proliferative effect on the six breast cancer cell lines tested, 3 ERalpha positive (MCF-7, T-47D, ZR-75-1) and 3 ERalpha negative (MDA-MB-231, SKBR-3, Hs578-T) whatever their ER (estrogen receptor) status. However, the mechanism of action of the ferrocenyl derivative appeared to differ depending on the status of the ERalpha.

Capacity of type I and II ligands to confer to estrogen receptor alpha an appropriate conformation for the recruitment of coactivators containing a LxxLL motif-Relationship with the regulation of receptor level and ERE-dependent transcription in MCF-7 cells.

Estrogen receptor alpha (ERalpha) belongs to the superfamily of nuclear receptors and as such acts as a ligand-modulated transcription factor. Ligands elicit in ERalpha conformational changes leading to the recruitment of coactivators required for the transactivation of target genes via cognate response elements. In many cells, activated ERalpha also undergoes downregulation by proteolysis mediated by the ubiquitin/proteasome system.

Trophic effect in MCF-7 cells of ERalpha17p, a peptide corresponding to a platform regulatory motif of the estrogen receptor alpha--underlying mechanisms.

As yet, estrogen receptor alpha (ERalpha) inhibitors used in clinical practice target a unique site, i.e. the hormone-binding pocket.

Fluorous tolerance of the estrogen receptor alpha as probed by 11-polyfluoroalkylestradiol derivatives.

The concern of this work was to try to delineate factors, inherent to fluorination, susceptible to influence estradiol binding to the estrogen receptor alpha (ERalpha). For this purpose, fluorinated chains were linked at 11beta position of the steroid (i.e.

Effects of (R,S)/(S,R)-4,5-bis(2-chloro-4-hydroxyphenyl)-2-imidazolines and (R,S)/(S,R)-2,3-bis(2-chloro-4-hydroxyphenyl)piperazines on estrogen receptor alpha level and transcriptional activity in MCF-7 cells.

4,5-Diaryl-2-imidazolines (Im(s)) and 2,3-diarylpiperazines (Pip(s)) belong to the type II class of estrogens. These compounds enhance ERalpha-mediated transcription of ERE-driven reporter genes in MCF-7 cells but do not compete with [(3)H]estradiol (E(2)) for receptor binding, because of distinct anchoring modes. The present study examined whether the estrogenic action of Im(s) and Pip(s) is associated with a down regulation of ERalpha, as reported for conventional agonists.

Effect of nuclear export inhibition on estrogen receptor regulation in breast cancer cells.

We used the Crm1 inhibitor leptomycin B (LMB) to examine a possible involvement of nuclear export in estrogen receptor alpha (ER) level and function in MCF-7 breast carcinoma cells. As revealed by immunofluorescence microscopy and western blotting with anti-ER antibodies, LMB produced an accumulation of ER in cell nuclei. LMB also partly abrogated ER elimination resulting from Hsp90 disruption and 17beta-estradiol (E(2))-induced ER downregulation.

Estrogens decrease gamma-ray-induced senescence and maintain cell cycle progression in breast cancer cells independently of p53.

Purpose: Sequential administration of radiotherapy and endocrine therapy is considered to be a standard adjuvant treatment of breast cancer. Recent clinical reports suggest that radiotherapy could be more efficient in association with endocrine therapy. The aim of this study was to evaluate the estrogen effects on irradiated breast cancer cells (IR-cells).

Calmodulin-independent, agonistic properties of a peptide containing the calmodulin binding site of estrogen receptor alpha.

Calmodulin (CaM) contributes to estrogen receptor alpha (ER)-mediated transcription. In order to study the underlying mechanisms, we synthesized a peptide including the CaM binding site: ERalpha17p (P(295)-T(311)). This peptide inhibited ER-CaM association, unlike two analogs in which two amino acids required for CaM binding were substituted.

Synthesis, structure, and estrogenic activity of 4-amino-3-(2-methylbenzyl)coumarins on human breast carcinoma cells.

A number of coumarins exhibit interesting pharmacological activities and are therefore of therapeutic use. We report here the synthesis and the structural analysis of new N-substituted 4-amino-3-(2-methylbenzyl)coumarins (compounds 8a-8e) that present structural analogies with estrothiazine and 11- or 7-substituted 17beta-estradiol. These derivatives were tested with respect to estrogenic activity on the estrogen receptor positive (ER+) human MCF-7 breast cancer cell line.

Loss of antagonistic activity of tamoxifen by replacement of one N-methyl of its side chain by fluorinated residues.

Efforts to limit the metabolic alteration of the aminoalkyl side chain of tamoxifen by fluorination largely decrease its ER-mediated antagonistic properties in MCF-7 cells (i.e., ability to inhibit growth, to stabilize ER, and to modulate ERE and AP-1 transcriptional activity).

Stimulatory effect of genistein and apigenin on the growth of breast cancer cells correlates with their ability to activate ER alpha.

Genistein and apigenin are phytoestrogens present in commercial preparations used for the treatment of postmenopausal symptoms. In this study, we assessed the influence of these compounds on mammary tumor growth. Both compounds stimulate the proliferation of MCF-7 and T47D cells [estrogen receptor alpha (ERalpha-positive)], but do not stimulate the proliferation of an ERalpha-negative cell line (MDA-MB-435 cells).

Estrogen receptor alpha: impact of ligands on intracellular shuttling and turnover rate in breast cancer cells.

Estrogen receptors (alpha and beta) are members of the steroid/thyroid nuclear receptors superfamily of ligand-dependent transcription factors. Impact of the alpha isoform of estrogen receptor (ER) on breast cancer etiology and progression is now well established. Current therapeutic strategy to treat ER-positive breast cancer relies on the blockade of ER trancriptional activity by antiestrogens.

Role of the proteasome in the regulation of estrogen receptor alpha turnover and function in MCF-7 breast carcinoma cells.

Estrogen receptor alpha (ER) turnover in MCF-7 cells was assessed by pulse chase analysis and measurement of ER steady-state level. In untreated cells, degradation of (35)S-labeled ER was characterized by a slow phase followed by a more rapid decline. Without ligand, ER elimination was totally compensated by synthesis which maintained receptor homeostasis.

Mechanisms governing the accumulation of estrogen receptor alpha in MCF-7 breast cancer cells treated with hydroxytamoxifen and related antiestrogens.

This study aimed at a better understanding of estrogen receptor alpha (ER) up regulation induced by partial estrogen antagonists. Effect of treatment with hydroxytamoxifen (OH-Tam) on ER level in MCF-7 cells was investigated by an approach combining ER measurement (enzyme immunoassay) and morphological demonstration (immunofluorescence). Furthermore, the influence of drug exposure on the rates of ER synthesis and degradation was assessed by determining [35S]methionine incorporated into the receptor in different experimental conditions (measurement of synthesis or pulse-chase experiments).

Tamoxifen derivatives for delivery of the antitumoral (DACH)Pt group: selective synthesis by McMurry coupling, and biochemical behaviour.

The goal of our study was to potentiate the effects of the ((R,R)-trans-1,2-diaminocyclohexane)-platinum(II) fragment [(DACH)Pt], known for its cytotoxic properties, either with tamoxifen (Tam), the most widely used antiestrogen in the treatment of hormone-dependent breast cancers, or with its active metabolite hydroxytamoxifen (hydroxy-Tam). We coupled Tam or hydroxy-Tam derivatives bearing a malonato group at the para position of the beta aromatic ring with the (DACH)Pt fragment. The malonato-Tam and malonato-hydroxy-Tam compounds were prepared through McMurry coupling of the appropriate ketones.

Estrogenic effect of a series of bisphenol analogues on gene and protein expression in MCF-7 breast cancer cells.

Bisphenols constitute a family of compounds, which includes many substances that have as a common chemical structure two phenolic rings joined together through a bridging carbon. In the present study, we aimed to determine whether several events triggered by 17 beta-estradiol (E(2)) in MCF-7 breast cancer cells were also observed in response to various bisphenol-A (BPA) analogues. We studied the expression of estrogen controlled genes by measuring the induction of pS2 (mRNA and protein) and progesterone receptor (PgR) as well as the expression of a luciferase reporter gene transfected into MVLN cells.

Pharmacological profile of 6,12-dihydro-3-methoxy-1-benzopyrano[3,4-b] [1,4]benzothiazin-6-one, a novel human estrogen receptor agonist.

Pharmacological studies were carried out to characterize further the endocrinological profile and the binding mode to the estrogen receptor (ER) of 6,12-dihydro-3-methoxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one (1). Binding experiments were conducted with highly purified recombinant human estrogen receptors hERa and beta. Potent estrogenic activity of compound 1 was assessed by testing its ability to down-regulate ERs and to enhance estrogen receptor element (ERE)-dependent transcription.