ABSTRACT. Grain shape and weight are the most important components of rice yield and are controlled by quantitative trait loci (QTLs). In this study, a double-haploid population, derived from the cross of japonica CJ06 and indica TN1, was used to analyze QTLs for grain shape and weight under two conditions: normal growth with unbroken husk and removing partial husk after flowering. Correlation analysis revealed that these traits, except grain weight, had a connection between the two conditions. Twenty-nine QTLs for grain shape and weight were detected on chromosomes 1 to 3; 6; 8 to 10; and 12, with the likelihood of odds value ranging from 2.38 to 5.36, including 10 different intervals. Some intervals were specifically detected after removing partial husk. The results contribute to the understanding of the genetic basis of grain filling and growth regulation, and provide us some assistance for improving grain plumpness in rice breeding.
Background: Resistance to endocrine therapy is a major clinical issue. The transcription factor AP-1 is a key regulator of cell growth and survival as well as a downstream signaling component of several pathways deregulated in endocrine-resistant breast cancer. We have previously shown that acquired endocrine resistance is associated with increased AP-1 activity. AP-1 has also been shown to interact with and modulate the ER network and transcriptional program, especially under hyperactive growth factor signaling, which is commonly associated with endocrine resistance. We hypothesized that interfering with AP-1 function would circumvent endocrine resistance possibly due to its role in modulating ER transcriptional activity. Methods and results: We inhibited AP-1 function by a genetic approach. We used two different MCF7 clones stably transfected with a Doxycycline (Dox)-inducible dominant-negative (DN) c-Jun (MCF7/Tet-Off Tam67 clones 62 and 67) and two vector-alone control MCF7 clones. Xenografts of these clones were established in ovariectomized nude mice supplemented with estrogen (E2). Mice were then randomized to continued E2 supplementation (control) or to endocrine therapy with either estrogen deprivation (ED) or tamoxifen (Tam), all in the presence or absence of Dox to induce the DN c-Jun expression. AP-1 blockade in both MCF7/Tet-Off Tam67 clones significantly enhanced sensitivity to Tam by reducing time to tumor size halving (p=.014 and p=.006 for clone 62 and 67, respectively) and time to complete tumor disappearance (p=.001 and p=.0034 for clone 62 and 67, respectively). Similar results were obtained with ED treatment. In addition, AP-1 blockade significantly delayed the onset of Tam resistance by increasing time to tumor size doubling (p=.0028). Furthermore, induction of DN c-Jun resulted in a dramatic shrinkage of growing tumors after long-term Tam treatment, suggesting reversal of endocrine resistance with AP-1 blockade. None of the above effects was observed in control clones upon Dox removal. Interestingly, no significant effect of AP-1 blockade was observed on E2-stimulated tumor growth. IHC analysis showed that AP-1 blockade induced tumor response by reducing proliferation (i.e., decreased % of Ki67- and phospho-Histone 3-positive cells) and by inducing apoptosis (i.e., increased % of cleaved caspase 3/7-positive cells). Bioinformatic analyses were conducted to intersect our MCF7 xenograft/Tam-resistant gene signature and the datasets of genes associated with ER DNA-binding sites obtained by whole-genome ER cistromic analysis under estrogen or epidermal growth factor (EGF) stimulation of MCF7 cells. A significant enrichment of the genes associated with the EGF-unique ER DNA-binding sites was observed within our Tam-resistant signature (p<2E-16). Remarkably, 90% of these DNA binding sites harbored an AP-1 motif. Conclusions: We show that AP-1 blockade increases tumor sensitivity and circumvents resistance to endocrine therapy, thus warranting the development of AP-1-targeted therapy to improve endocrine treatment outcomes. Overall, we suggest that AP-1 is critical in induction of a switch in the ER transcriptional program and may be a new hallmark of endocrine resistance. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-18.
Background: The estrogen receptor (ER) is expressed in ∼70% of sporadic breast cancer and activates genes driving cell proliferation and tumorigenesis. We have previously performed genome-wide analysis of ER binding sites in MCF-7 breast cancer cells, and identified distinct mechanisms of ER signaling. We have also previously used EpCAM and CD49f as markers to enrich for viable ER-positive (ER+) cells obtained from non malignant breast tissue. Here, we seek to elucidate differences in ER signaling between non-malignant and ER+ breast cancer cells. Methods: Primary breast epithelial cells were obtained from patients undergoing reduction mammoplasties and surgical excision of ER+ breast cancer. After dissociation of breast reductions into a single-cell suspension, ER+ mature luminal (ML; EpCAM+CD49f−) and luminal progenitor (LP; EpCAM+CD49f+) subpopulations were obtained by flow cytometry. Following estrogen stimulation, RNA was extracted for gene microarray analysis. ER chromatin immunoprecipitation and DNA sequencing (ChIP-seq) was performed. These results were compared to MCF-7 breast cancer cells. Results: Reduction mammoplasty and ER+ breast cancer tissues were analyzed, and compared to MCF-7 cells. Gene expression profiles were different between non-malignant tissue and ER+ breast cancer cells following estrogen stimulation, with a 2–3 fold higher number of ER regulated genes in ER+ breast cancer compared to ER+ non malignant cells, and few overlapping estrogen regulated genes. Genes that promotes cell cycling and cell proliferation were downregulated in non-malignant tissue, but were upregulated in breast cancer cells (P < 10–5). CYP1A1, a major estradiol metabolizing enzyme, was upregulated in normal cells but downregulated in ER+ breast cancer cells. Motif analysis of ER ChIP-seq data in normal and ER+ breast cancer tissues demonstrated an enrichment of ER motifs in the overlapping sites and an enrichment of FOXA1 motifs in ER+ breast cancer cells and TCF12 motifs in non-malignant ER+ epithelial cells. Conclusions: There are contrasting differences in ER signaling between normal mammary and breast cancer cells, with estrogen having anti-proliferative effects in normal luminal cells compared to pro-proliferative effects in breast cancer. ER ChIP-Seq has identified TCF12 as a major co-factor in non-malignant breast tissue whilst FOXA1 is a major co-factor in ER+ breast cancer. Our data provides evidence for key alterations in ER-signaling during tumorigenesis, and identifies potential mechanisms to target cancer specific ER signaling. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD01-08.
Introduction: Advancements in molecular biology have unveiled multiple breast cancer promoting pathways and potential therapeutic targets. Large randomized clinical trials remain the ultimate means of validating therapeutic efficacy, but they require large cohorts of patients and are lengthy and costly. An alternative approach is to conduct a window of opportunity study in which patients are exposed to a drug pre-surgically during the interval between the core needle biopsy (CNB) and the definitive surgery (excisional biopsy (EB)). These are non-therapeutic studies and the end point is not clinical or pathological response but rather evaluation of molecular changes in the tumor specimens that can predict response. However, since the end points of the non-therapeutic studies are biologic, it is critical to first define any biologic changes that occur in the absence of treatment. In this study, we compared the molecular profiles of breast cancer tumors at the time of the diagnostic biopsy versus the definitive surgery in the absence of any intervention. Methods: The study was conducted with DFCI/HCC IRB approval and patient consent. Post-menopausal women with a breast lesion suspected to be cancerous were eligible for this study. We obtained a tissue specimen at the time of a CNB and if determined to be consistent with invasive carcinoma a second specimen was obtained at the time of the EB. We used the Nanostring Ncounter system to study the expression level of 148 transcripts. Since we expected that most of the tumors will be hormone receptor positive (HR+), the library included; genes that have been shown to be prognostic in HR+ tumors (Oncotype DX®, PAM50), estrogen receptor (ER) modulators, ER responsive genes and inflammatory genes. The Wilcoxon's signed rank test was used to evaluate for changes in gene expression levels between the paired samples. Results: 25 patients were enrolled in this study and paired tumor tissue samples were obtained from all patients. 21 of the paired samples were successfully analyzed by the nanostring system. 86% of the patients are HR+/Her2−. We found that the gene expression levels of 14 out of the 148 genes (9%) did change between the CNB and EB without any intervention (p < 0.05). 8 of these 14 genes can be classified as inflammatory genes that also have known functions in tumor progression. The expression of these 8 genes was upregulated between the biopsies and include; CD68, ADM, CD14, IL6, VEGFA, CD52, CD44 and SNAI1. These changes may be due to an inflammatory response to the CNB. Ki67 expression did not change significantly between biopsies. Conclusions: In this study we found significant gene expression variations between CNBs and EBs in 9% of the genes tested, without any therapeutic intervention. Our findings suggest that when conducting a “Window of Opportunity” clinical study to evaluate for biomarkers of response or resistance, changes in expression of inflammatory genes cannot be attributed to treatment and a control arm should be considered. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-07-07.
Redundant mechanisms support IgA responses to intestinal antigens. These include multiple priming sites (mesenteric lymph nodes (MLN), Peyer's patches and isolated lymphoid follicles) and various cytokines that promote class switch to IgA, even in the absence of T cells. In spite of these back-up mechanisms, vaccination against enteric pathogens such as Rotavirus has limited success in some populations. Genetic and environmental signals experienced during early life are known to influence mucosal immunity, yet the mechanisms for how these exposures operate remain unclear. Here we used Rotavirus infection to follow antigen-specific IgA responses through time and in different gut compartments. Using genetic and pharmacological approaches, we tested the role of a pathway known to support IgA responses (Lymphotoxin -LT) at different developmental stages. We found that LT-beta receptor (LTβR) signalling in utero programs intestinal IgA responses in adulthood by affecting antibody class switch recombination to IgA and subsequent generation of IgA antibody-secreting cells within an intact MLN. In addition, in utero LTβR signalling dictates the phenotype and function of MLN stromal cells in order to support IgA responses in the adult. Collectively, our studies uncover new mechanistic insights into how in utero LTβR signalling impacts mucosal immune responses during adulthood.
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