Nuclear ErbB-2: a Novel Therapeutic Target in ErbB-2-Positive Breast Cancer?

Membrane overexpression of ErbB-2 (MErbB-2), a member of the ErbB family of receptor tyrosine kinases, occurs in 15-20% of breast cancers (BC) and constitutes a therapeutic target in this BC subtype (ErbB-2-positive). Although MErbB-2-targeted therapies have significantly improved patients' clinical outcome, resistance to available drugs is still a major issue in the clinic. Lack of accurate biomarkers for predicting responses to anti-ErbB-2 drugs at the time of diagnosis is also an important unresolved issue.

Distribution of FMR1 and FMR2 Repeats in Argentinean Patients with Primary Ovarian Insufficiency.

The premutation state of (Fragile X Mental Retardation 1) has been associated with primary ovarian insufficiency (POI), and is the most common known genetic cause for 46,XX patients. Nevertheless, very few studies have analyzed its frequency in Latin American populations. Additionally, a relationship between alleles carrying a cryptic microdeletion in the 5'UTR of and the onset of POI has only been studied in one population.

Misregulation effect of a novel allelic variant in the Z promoter region found in cis with the CYP21A2 p.P482S mutation: implications for 21-hydroxylase deficiency.

The aim of the current study was to search for the presence of genetic variants in the CYP21A2 Z promoter regulatory region in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Screening of the 10 most frequent pseudogene-derived mutations was followed by direct sequencing of the entire coding sequence, the proximal promoter, and a distal regulatory region in DNA samples from patients with at least one non-determined allele. We report three non-classical patients that presented a novel genetic variant-g.

Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy.

Introduction: The role of the progesterone receptor (PR) in breast cancer remains a major clinical challenge. Although PR induces mammary tumor growth, its presence in breast tumors is a marker of good prognosis. We investigated coordinated PR rapid and nonclassical transcriptional effects governing breast cancer growth and endocrine therapy resistance.

Expression of fragile X mental retardation protein and Fmr1 mRNA during folliculogenesis in the rat.

Fragile X mental retardation protein (FMRP) belongs to a small family of RNA-binding proteins. Its absence or inactivity is responsible for fragile X syndrome, the most common cause of inherited mental retardation. Despite its ubiquitous expression, FMRP function and expression remain almost understudied in non-neuronal tissues, though previous studies on germline development during oogenesis may suggest a special function of this protein also in ovarian tissue.

Targeting Stat3 induces senescence in tumor cells and elicits prophylactic and therapeutic immune responses against breast cancer growth mediated by NK cells and CD4+ T cells.

Aberrant Stat3 activation and signaling contribute to malignant transformation by promoting cell cycle progression, inhibiting apoptosis, and mediating tumor immune evasion. Stat3 inhibition in tumor cells induces the expression of chemokines and proinflammatory cytokines, so we proposed to apply Stat3-inhibited breast cancer cells as a source of immunogens to induce an antitumor immune response. Studies were performed in two murine breast cancer models in which Stat3 is activated: progestin-dependent C4HD cells and 4T1 cells.

Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer.

Background: The biological relevance of nuclear ErbB-2/HER2 (NuclErbB-2) presence in breast tumors remains unexplored. In this study we assessed the clinical significance of ErbB-2 nuclear localization in primary invasive breast cancer. The reporting recommendations for tumor marker prognostic studies (REMARK) guidelines were used as reference.

Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most frequent inborn error of metabolism, and accounts for 90-95% of CAH cases. The affected enzyme, P450C21, is encoded by the CYP21A2 gene, located together with a 98% nucleotide sequence identity CYP21A1P pseudogene, on chromosome 6p21.3.

Novel role of signal transducer and activator of transcription 3 as a progesterone receptor coactivator in breast cancer.

Interactions between progesterone receptor (PR) and signal transducer and activator of transcription 3 (Stat3)-mediated signaling pathways have already been described. In the present study, we explored the capacity of Stat3 to functionally interact with progesterone receptor (PR) and modulate PR transcriptional activation in breast cancer cells. We found that the synthetic progestin medroxyprogesterone acetate (MPA) induced the association of a PR/Stat3 complex in which Stat3 acts as a coactivator of PR.

Progesterone receptor induces ErbB-2 nuclear translocation to promote breast cancer growth via a novel transcriptional effect: ErbB-2 function as a coactivator of Stat3.

Progesterone receptor (PR) and ErbB-2 bidirectional cross talk participates in breast cancer development. Here, we identified a new mechanism of the PR and ErbB-2 interaction involving the PR induction of ErbB-2 nuclear translocation and the assembly of a transcriptional complex in which ErbB-2 acts as a coactivator of Stat3. We also highlighted that the function of ErbB-2 as a Stat3 coactivator drives progestin-induced cyclin D1 promoter activation.

Transactivation of ErbB-2 induced by tumor necrosis factor alpha promotes NF-kappaB activation and breast cancer cell proliferation.

Tumor necrosis factor alpha (TNFalpha) is a pleiotropic cytokine which, acting locally, induces tumor growth. Accumulating evidence, including our findings, showed that TNFalpha is mitogenic in breast cancer cells in vitro and in vivo. In the present study, we explored TNFalpha involvement on highly aggressive ErbB-2-overexpressing breast cancer cells.

Activation of Stat3 by heregulin/ErbB-2 through the co-option of progesterone receptor signaling drives breast cancer growth.

Cross talk between the steroid hormone receptors for estrogen and progesterone (PR) and the ErbB family of receptor tyrosine kinases appears to be a hallmark of breast cancer growth, but its underlying mechanism remains poorly explored. Here we have highlighted signal transducer and activator of transcription 3 (Stat3) as a key protein activated by heregulin (HRG), a ligand of the ErbB receptors, through co-opted, ligand-independent PR function as a signaling molecule. Stat3 activation was an absolute requirement in HRG-induced mammary tumor growth, and targeting Stat3 effectively inhibited growth of breast cancer cells with activated HRG/ErbB-2 and PR.

TNF alpha acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-kappa B-dependent pathways.

Tumor necrosis factor alpha (TNF alpha) enhances proliferation of chemically-induced mammary tumors and of T47D human cell line through not fully understood pathways. Here, we explored the intracellular signaling pathways triggered by TNF alpha, the participation of TNF alpha receptor (TNFR) 1 and TNFR2 and the molecular mechanism leading to breast cancer growth. We demonstrate that TNFalpha induced proliferation of C4HD murine mammary tumor cells and of T47D cells through the activation of p42/p44 MAPK, JNK, PI3-K/Akt pathways and nuclear factor-kappa B (NF-kappa B) transcriptional activation.

Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways.

Accumulating evidence indicates that progestins are involved in controlling mammary gland tumorigenesis. Here, we assessed the molecular mechanisms of progestin action in breast cancer models with different phenotypes. We examined C4HD cells, an estrogen (ER) and progesterone (PR) receptor-positive murine breast cancer model in which progestins exert sustained proliferative response, the LM3 murine metastatic mammary tumor cell line, which lacks PR and ER expression, and human PR null T47D-Y breast cancer cells.

Alpha-enolase: a novel autoantigen in patients with premature ovarian failure.

Objective: Although controversial, the presence of circulating antiovarian antibodies (AOA) may be considered a marker of autoimmune premature ovarian failure (POF). The purpose of the present work was to evaluate the presence of AOA in POF patients, and to identify a possible autoantigen in order to develop a reliable diagnostic tool that might help to determine the real prevalence of autoimmune POF.

Design: Non-randomised study.

Immunization with murine breast cancer cells treated with antisense oligodeoxynucleotides to type I insulin-like growth factor receptor induced an antitumoral effect mediated by a CD8+ response involving Fas/Fas ligand cytotoxic pathway.

We have demonstrated that in vivo administration of phosphorothioate antisense oligodeoxynucleotides (AS[S]ODNs) to type I insulin-like growth factor receptor (IGF-IR) mRNA resulted in inhibition of C4HD breast cancer growth in BALB/c mice. The present study focused on whether in vivo administration of C4HD tumor cells pretreated with IGF-IR AS[S]ODN and irradiated could provide protection against C4HD wild-type tumor challenge and also on elucidating the mechanism mediating this effect. Our results showed that mice immunized with IGF-IR AS[S]ODN-treated C4HD cells experienced a growth inhibition of 53.

Breast cyst fluids increase the proliferation of breast cell lines in correlation with their hormone and growth factor concentration.

Objective And Design: Gross cystic disease (GCD) of the breast is reported to occur in 7% of women in the developed world and, although not premalignant, is thought to be associated with an increased risk of breast cancer. Hormone and growth factor concentration levels were measured in breast cyst fluid (BCF) to correlate them with their mitogenic activity in tumour (MCF-7) or nontransformed (MCF-10A) cells.

Results: Oestradiol (E2), oestrone (E1), E2-sulfate (E2-S), E1-sulfate (E1-S) and epidermal growth factor (EGF) concentrations were, as expected, significantly higher in type I than in type II cysts, while transforming growth factor-beta 2 (TGF-beta2) showed higher levels in type II cysts.

Controversial role of inhibin alpha-subunit gene in the aetiology of premature ovarian failure.

Background: Premature ovarian failure (POF) is characterized by hypergonadotropic amenorrhoea before the age of 40. Inhibin alpha-subunit (INHalpha) gene is proposed as a candidate gene due to its role in negative feedback control of FSH.

Methods: Polymorphism -16C>T of INHalpha gene was studied in 61 POF patients and 82 controls above 40 years old (C > 40).