Adjuvant endocrine therapy in pre- versus postmenopausal patients with steroid hormone receptor-positive breast cancer: results from a large population-based cohort of a cancer registry.

PURPOSE: Adjuvant endocrine therapy (ET) is indicated in patients with steroid hormone receptor (HR)-positive breast cancer. The aim of this study was to evaluate the quality of HR determination and adjuvant endocrine treatment of breast cancer patients in a large cohort of more than 7000 women by analyzing data from a population-based regional cancer registry. METHODS: Data from the Clinical Cancer Registry Regensburg (Bavaria, Germany) were analyzed. Female patients with primary, nonmetastatic invasive breast cancer who were diagnosed between 2000 and 2012 (n = 7421) were included. HR-status was available in 97.4 % (n = 7229) of the patients. This data set (n = 7229) was used for subsequent statistical analyses. RESULTS: Since 2009, almost a complete rate of 99.6 % of analyzed HR-status was achieved. In sum, 85.8 % of the patients (n = 6199) were HR-positive, whereas 14.2 % (n = 1030) were HR-negative. Overall, 85.3 % (n = 5285) of HR-positive patients received ET either alone or in combination with chemotherapy (CHT) and/or trastuzumab. The majority of premenopausal patients received CHT plus ET (716 patients, 52.3 %). In postmenopausal patients, the most frequent systemic therapy was ET alone (2670 patients, 55.3 %). Best overall survival (OS) was found in HER2-/HR-positive patients receiving CHT plus ET plus trastuzumab (7-year OS rate of 97.2 % in premenopausal patients versus 86.9 % in postmenopausal patients). Premenopausal patients had a reduced benefit from additional CHT than postmenopausal patients. Premenopausal patients receiving only ET had a 7-year OS rate of 95.3 % compared to 92.7 % of patients receiving CHT plus ET. In contrast, postmenopausal patients treated with CHT plus ET had a 7-year OS rate of 84.0 % in comparison with those patients receiving only ET with a 7-year OS rate of 81.7 %. CONCLUSIONS: Analysis of HR in patients with early breast cancer achieved a very high quality in recent years. The vast majority of HR-positive patients received ET, and this guideline-adherent use improved OS. Inverse effects of the CHT plus ET combination in premenopausal versus postmenopausal patients and a still existing minority of patients not receiving guideline-adherent treatment should be further investigated in future studies.

Receptors for luteinizing hormone-releasing hormone (GnRH) as therapeutic targets in triple negative breast cancers (TNBC).

Triple negative breast cancers express receptors for gonadotropin-releasing hormone (GnRH) in more than 50% of the cases, which can be targeted with peptidic analogs of GnRH, such as triptorelin. The current study investigates cytotoxic activity of triptorelin as a monotherapy and in treatment combinations with chemotherapeutic agents and inhibitors of the PI3K and the ERK pathways in in vitro models of triple negative breast cancers (TNBC). GnRH receptor expression of TNBC cell lines MDA-MB-231 and HCC1806 was investigated. Cells were treated with triptorelin, chemotherapeutic agents (cisplatin, docetaxel, AEZS-112), PI3K/AKT inhibitors (perifosine, AEZS-129), an ERK inhibitor (AEZS-134), and dual PI3K/ERK inhibitor AEZS-136 applied as single agent therapies and in combinations. MDA-MB-231 and HCC1806 TNBC cells both expressed receptors for GnRH on messenger (m)RNA and protein level and were found sensitive to triptorelin with a respective median effective concentration (EC50) of 31.21 ± 0.21 and 58.50 ± 19.50. Synergistic effects occurred when triptorelin was combined with cisplatin. In HCC1806 cells, synergy occurred when triptorelin was applied with PI3K/AKT inhibitors perifosine and AEZS-129. In MDA-MB-231 cells, synergy was observed after co-treatment with triptorelin and ERK inhibitor AEZS-134 and dual PI3K/ERK inhibitor AEZS-136. GnRH receptors on TNBC cells can be used for targeted therapy of these cancers with GnRH agonist triptorelin. Treatment combinations based on triptorelin and PI3K and ERK inhibitors and chemotherapeutic agent cisplatin have synergistic effects in in vitro models of TNBC. If confirmed in vivo, clinical trials based on triptorelin and cisplatin could be quickly carried out, as triptorelin is FDA approved for other indications and known to be well tolerated.

Nuclear estrogen receptors co-activation mechanisms.

Estrogens play very important role in opening the transcription event, which is a final step of activation of the first order mediators as receptors or channels in the cell wall by information coming from the outside of the cell. For the long time the exact step by step mechanism of cellular transfer of information to the cell nuclei was not known. Currently many new informations are available. Very important seems the step of phosphorylation and therefore desensitization of the target proteins. All peptide kinases, especially serine and threonine, like protein kinases A and C, RAS and MAP kinases, cycline kinases are potential or confirmed biological targets. Except them elements of the transcription complexes like p160.SRC-1, histon acetyltransferase and histon deacetylase, CBP/p300, TRAP/DRIP, NSD1, PPARγ/PGC-1, NCOR1, SMRT, REA were also found useful. Finally estrogens are able to activate other receptors, namely aryl hydrocarbon receptors (AhR) and estrogen receptor related proteins (ERR). It is well known that many types of cancer are related to the direct or indirect excessive activation of nuclear estrogen receptors, therefore their inhibition could be crucial in many estrogen-related cancers. Understanding the interactions in such complexes would help in developing new and better multi-target cures and finding new ligands with better pharmacological and pharmacokinetic properties.

Expression of the lipid transporters ABCA3 and ABCA1 is diminished in human breast cancer tissue.

ATP-binding cassette transporters ABCA3 and ABCA1 are related to a differentiated, lipid-secreting phenotype of type II pneumocytes. Since mammary gland epithelial cells also show pronounced lipid metabolism and secretion, we investigated the expression of these proteins in normal as well as in neoplastic breast tissue. Normal human breast tissue, breast cancer cell lines, and 162 tumor samples of patients with primary unilateral invasive breast cancer were analyzed for ABCA3 and ABCA1 protein expression by immunohistochemistry using tissue microarrays. Strong ABCA3 and ABCA1 expression was found in the inner layer of normal mammary gland epithelium. Concurrent cytoplasmic ABCA3 and ABCA1 immunoreactivity was found in 9 of 11 breast cancer cell lines. ABCA3 and ABCA1 were shown to be differentially expressed in human breast cancer. Loss of ABCA3 staining was significantly associated with positive nodal status and negative progesterone receptor expression. In multivariate analysis, diminished ABCA3 expression proved to be a significant, independent and adverse risk factor for tumor recurrence. ABCA1 expression was associated with positive lymph nodes, but not significantly associated with tumor recurrence or breast cancer-specific survival. ABCA3 and ABCA1 are strongly expressed in normal mammary gland epithelium. Decreased ABCA3 expression in breast cancer seems to be associated with poor prognosis.

Adiponectin differentially affects gene expression in human mammary epithelial and breast cancer cells.

Serum levels of adiponectin are inversely associated with breast cancer risk. In this study, its effect on growth and gene expression of MCF-7 breast cancer cells and MCF-10A human mammary epithelial cells was compared. The antiproliferative effect of adiponectin on MCF-10A cells was more pronounced and was accompanied by elevated transcript levels of caspase 1, ERbeta2, ERbeta5, TR2 and USP2. Our data suggest that upregulation of genes with known growth inhibitory or apoptotic functions in mammary epithelial cells might contribute to the protective action of this adipocytokine.

Regulation of GnRH I receptor gene expression by the GnRH agonist triptorelin, estradiol, and progesterone in the gonadotroph-derived cell line alphaT3-1.

The secretion of luteinizing hormone (LH) and the GnRH receptor (GnRH-R) concentration are modulated by ovarian steroids and GnRH. To elucidate whether this regulation is due to alterations at the transcriptional level, we examined the GnRH I-R mRNA expression in the gonadotroph-derived cell line alphaT3-1 treated with different estradiol and progesterone paradigms and the GnRH I agonist triptorelin. alphaT3-1 cells were treated with different steroid paradigms: 1 nM estradiol or 100 nM progesterone for 48 h alone or in combination. Cells were exposed to 10 nM or 100 pM triptorelin for 30 min, 3 h, 9 h, or, in pulsatile way, with a 5-min pulse per hour. The GnRH I-R mRNA was determined by Northern blot analysis. GnRH I-R mRNA from cells treated with continuous triptorelin decreased in a time- and concentration-dependent manner. Pulsatile triptorelin increased GnRH I-R gene expression. Progesterone alone further enhanced this effect, whereas estradiol and its combination with progesterone diminished it. Continuous combined treatment with estradiol and progesterone lead to a significant decrease of GnRH I-R mRNA by 30% and by 35% for estradiol alone. The addition of 10 nM triptorelin for 30 min or 3 h could not influence that steroid effect. In conclusion, estradiol and progesterone exclusively decreased GnRH I-R mRNA in alphaT3-1 cells no matter whether they are treated additionally with the GnRH I agonist triptorelin. The enhanced sensitivity of gonadotrophs and GnRH I-R upregulation by estradiol is not due to increased GnRH I gene expression because GnRH I-R mRNA is downregulated by estradiol and progesterone. Other pathways of the GnRH I-R signal transduction might be involved.

[Estrogen receptor Beta isoforms -- functions and clinical relevance in breast cancer]. / Ostrogenrezeptor-beta-Isoformen--Funktionen und klinische Bedeutung bei Brustkrebs.

Estrogen receptors (ER) are hormone regulated transcription factors which mediate the cellular estrogen response. So far two types of ER could be identified, ERalpha and ERbeta. ERalpha plays an important role as a predictive factor for the effectiveness of endocrine agents in the treatment of breast cancer. Patients with ERalpha positive tumors receive adjuvant endocrine therapy. Recent findings indicate a crucial role of ERbeta and its isoforms for the prognosis of breast cancer. This paper reviews the current knowledge on the functions of ERbeta and its splice variants.

[Impact of the cellular estradiol response on the therapeutic inhibition of growth factor signaling]. / Einfluss der zellulären Ostradiolantwort auf die therapeutische Inhibition von Wachstumsfaktor-Signalwegen.

Cellular response to estradiol stimuli ist mediated by different signal transduction cascades. In addition to classical mechanisms like the activation of estrogen response elements, there is increasing interest in the so-called non- nuclear actions of estrogens. It has been shown, that the estradiol-induced activation of cytoplasmic kinases is an important alternative mechanism of the cellular estradiol response. Consequently, the question has been raised, whether estradiol-induced activation of growth factor signaling would be able to interfere with the action of antitumoral substances directed against receptor-tyrosine kinase signal transduction. Recent data demonstrated, that estradiol is able to diminish the effects of antitumoral drugs targeting the HER2 receptor in vitro. Novel insights into the non-nuclear estradiol response and its impact on the efficacy of antitumoral drugs observed in endometrial tumor cells are reviewed.

The activation of an extracellular signal-regulated kinase by oestradiol interferes with the effects of trastuzumab on HER2 signalling in endometrial adenocarcinoma cell lines.

Cellular response to oestradiol stimuli is mediated both by oestrogen receptor (ER) binding to oestrogen response elements (EREs) and by non-nuclear actions like activation of mitogen-activated protein kinase (MAPK) signal transduction. Therefore, oestradiol stimuli might be able to interfere with the action of antitumoral substances directed against receptor tyrosine kinase signalling. We investigated the effect of oestradiol on the inhibition of HER2 signalling by trastuzumab (Herceptin) in two human endometrial adenocarcinoma cell lines. Activation of the extracellular signal-regulated kinase (ERK-1/2), a major mediator of HER2 signalling, was measured by means of western blotting experiments and ERE activation was determined in transient reporter-gene assays. In endometrial Ishikawa and HEC-1A adenocarcinoma cells, HER2 signalling was inhibited by trastuzumab only in the absence of oestradiol. We were able to demonstrate that oestradiol counteracted the inhibitory effects of trastuzumab by rapid phosphorylation of ERK-1/2, a kinase downstream of the HER2 receptor. The pure anti-oestrogen ICI 182,780 was able to restore both the trastuzumab-triggered inhibition of the ERK-1/2 pathway and the antiproliferative action of this substance in Ishikawa cells. Our data suggest that combinations of trastuzumab with anti-oestrogens may be effective in the treatment of endometrial cancers with a positive ER and HER2 receptor status.

A novel basement membrane-induced gene identified in the human endometrial adenocarcinoma cell line HEC1B.

Cultured HEC1B human endometrial adenocarcinoma cells respond to reconstituted basement membrane (Matrigel) by morphological and functional differentiation in vitro. Our goal is to identify genes involved in this differentiation process. By means of rt-PCR, we were able to isolate the novel 2.4 kb Matrigel-induced transcript icb-1 containing an open reading frame predicting a 31.7 kDa protein. The time-dependent induction of icb-1 gene expression by basement membrane was confirmed by Northern blot experiments. In a data bank search, several EST homologues corresponding to the 3' untranslated region could be found. In summary, icb-1 as a new tool enables us to study molecular mechanisms of cell-matrix interactions contributing to carcinogenesis.