Project description:Biopsies were collected from post-menopausal women with ER+ HER2- breast cancer who were subsequently treated with either letrozole or letrozole plus bevacizumab.
Project description:There is a lack of systematic investigations of large-scale transcriptome patterns associated with normal breast development. Herein, we profiled whole-transcriptome (by microarrays) of normal mammary glands in female Sprague-Dawley rats, an animal model widely used in breast cancer research, across six distinctive developmental stages – pre-pubertal, peri-pubertal, pubertal, lactation, and adult parous and age-matched nulliparous.
Project description:At birth, all female mice, including those that either lack estrogen receptor α (ERα-knockout) or that express mutated forms of ERα (AF2ERKI), have a hypoplastic uterus. However, uterine growth and development that normally accompanies pubertal maturation does not occur in ERα-knockout or AF2ERKI mice, indicating ERα mediated estrogen signaling is essential for this process. Mice that lack Cyp19 (aromatase, ArKO mice), an enzyme critical for estrogen (E2) synthesis, are unable to make E2, and lack pubertal uterine development. A single injection of E2 into ovariectomized adult (10 weeks old) females normally results in uterine epithelial cell proliferation, however, we observe that, although ERα is present in the ArKO uterine cells, no proliferative response is seen. We assessed the impact of exposing ArKO mice to E2 during pubertal and post-pubertal windows and observed that E2 exposed ArKO mice acquired growth responsiveness. Analysis of differential gene expression between unexposed ArKO samples and samples from animals exhibiting the ability to mount an E2-induced uterine growth response (WT or E2 exposed ArKO) revealed activation of EZH2 and HAND2 signaling and inhibition of GLI1 responses. EZH2 and HAND2 are known inhibit uterine growth, and GLI1 is involved in IHH signaling, which is a positive mediator of uterine response. Finally, we show that exposure of ArKO females to dietary phytoestrogens results in their acquisition of uterine growth competence. Altogether our findings suggest that pubertal levels of endogenous and exogenous estrogens impact biological function of uterine cells later in life via ERα-dependent mechanisms. We compared uterine RNA from ovariectomized adult aromatase knockout mice (ARKO) mice that were untreated to WT mice and to ARKO that were administered estradiol benzoate (EB) to induce uterine epithelial cell growth competence
Project description:Background: The exact nature of the interrelationship between pubertal brain development and hormones involvement has always attracted wide interest. Brain structural changes that occur during the pubertal developmental process mainly appear in the regions most closely linked with emotion, motivation and cognitive functions. Using a sheep model, we have previously shown that peri-pubertal pharmacological blockade of gonadotropin-releasing hormone (GnRH) receptors results in increased sex-differences in cognitive executive function and emotional control, as well as in a sex- and side-specific gene expression pattern of hippocampal genes associated with synaptic plasticity and endocrine signaling. In this study, we explore the effects of this treatment regime on the amygdalar gene expression profile. Methods: The study was conducted with 30 same-sex twin lambs (14 female and 16 male), half of which were treated with the GnRH agonist (GnRHa) goserelin acetate every 4th week, beginning before puberty, until 50 weeks of age. The gene expression profiles of left and right amygdala samples from all 30 animals were measured by using ovine 8 X 15 K Agilent microarrays. Furthermore, differential expression of a selected number of genes was confirmed by qRT-PCR (Quantitative real time PCR). Networking analyses and Gene Ontology (GO) Term analyses were performed with the Ingenuity Pathway Analysis (IPA), version 7.5 DAVID (Database for Annotation, Visualization and integrated Discovery) software packages respectively. Results: GnRHa treatment was associated with significant sex- and hemisphere-specific differential expression of genes. Interestingly, genome-wide transcription showed a set of 438 (p value <0.05) genes in female treated left and 46 (p value <0.0.5) genes in females treated right amygdala were differentially expressed but not in any treatment group of male animals. Conclusion: Our results indicate that GnRH directly and/or indirectly is involved in the regulation of sex- and side-specific differential expression of genes in amygdala. Hence, this finding should be considered when long-term peri-pubertal GnRHa treatment is used in children.
Project description:In the present investigation, we have exploited the opportunity provided by neoadjuvant treatment of a group of postmenopausal women with large operable or locally advanced breast cancer (in which therapy is given with the primary tumour remaining within the breast) to take sequential biopsies of the same cancers before and after 10-14 days treatment with letrozole. RNA extracted from the biopsies has been subjected to Affymetrix microarray analysis and the data from paired biopsies interrogated to discover genes whose expression is most influenced by oestrogen deprivation. Keywords: time course
Project description:Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women that is comprised of two out of the following three features: hyperandrogenism, oligo- or amenorrhea, or polycystic ovaries. In addition to infertility, many women with PCOS have metabolic dysregulation that increases the risk of developing type 2 diabetes, hypertension, and non-alcoholic fatty liver disease. Changes in the gut microbiome are associated with PCOS and gut microbes may be involved in the pathology of this disorder. Since PCOS often manifests in the early reproductive years, puberty is considered to be a critical time period for the development of PCOS. Exposure to sex steroid hormones during development results in permanent, organizational effects, while activational effects are transient and require the continued presence of the hormone. Androgens exert organizational effects during prenatal or early post-natal development, but it is unclear whether androgen excess results in organizational or activational effects during puberty. We recently developed a letrozole-induced PCOS mouse model that recapitulates both reproductive and metabolic phenotypes of PCOS. In this study, we investigated whether letrozole treatment of pubertal female mice exerts organizational or activational effects on host physiology and the gut microbiome. Two months after letrozole removal, we observed recovery of reproductive and metabolic parameters, as well as diversity and composition of the gut microbiome, indicating that letrozole treatment of female mice during puberty resulted in predominantly activational effects. These results suggest that if exposure to excess androgens during puberty leads to the development of PCOS, reduction of androgen levels during this time may improve reproductive and metabolic phenotypes in women with PCOS. These results also imply that continuous letrozole exposure is required to model PCOS in pubertal female mice since letrozole exerts activational rather than organizational effects during puberty.
Project description:Transcriptional profilling of the female primate hypothalamus during normal puberty. Total RNA samples from hypothalami from juvenile (JUV), early pubertal (EP) and mid pubertal (MP) female monkeys were used to compare pairwise against the JUV group. Keywords: Normal gene expression profiling
Project description:We tested the hypothesis that high FA (HFA) intake alters the juvenile/peri-pubertal mammary transcriptome in a manner consistent with increased potential for breast cancer, detectable beyond the period of intake. C57BL/6 mice were fed control FA (CFA) (1 mg/kg diet) or HFA (5 mg/kg diet) diets for 4 weeks, followed by AIN93M maintenance diet for 4 weeks. RNA sequencing of the mammary transcriptome (~83 million reads) showed 18 transcripts (17 downregulated) differentially expressed between groups. Gene Set Enrichment showed downregulated genes significantly enriched in oxidative phosphorylation, adipogenesis, fatty acid metabolism and epithelial mesenchymal transition. Cancer and developmental disorder were the most altered Disease and Disorder pathways, with top upstream regulators identified as DNA methyltransferases. This study demonstrates HFA intake during juvenile/peri-pubertal mammary development induces changes in the mammary transcriptome associated with altered energy metabolism, cell neoplasia and epigenetic regulation of gene.