Ruth Keri - Academia.edu (original) (raw)

Papers by Ruth Keri

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, 2006

Exposure of the fetus to excess estrogen is believed to increase the risk of developing breast ca... more Exposure of the fetus to excess estrogen is believed to increase the risk of developing breast cancer during adult life. Fetal exposure to low doses of the xenoestrogen bisphenol A resulted in long-lasting effects in the mouse mammary gland that were manifested during adult life. It enhanced sensitivity to estradiol, decreased apoptosis, increased the number of progesterone receptor-positive epithelial cells at puberty and increased lateral branching at 4 months of age. We now report that fetal exposure to 2.5, 25, 250 and 1000μg bisphenol A/kg body weight/day induces the development of ductal hyperplasias and carcinoma in situ at postnatal day 50 and 95 in rats. These highly proliferative lesions have an increased number of estrogen receptor-α positive cells. Thus, fetal bisphenol A exposure is sufficient to induce the development of preneoplastic and neoplastic lesions in the mammary gland in the absence of any additional treatment aimed at increasing tumor development.

ACS Biomaterials Science & Engineering, 2017

The Ebola virus (EBOV) causes a highly virulent and deadly disease. The 2014 Ebola outbreak in We... more The Ebola virus (EBOV) causes a highly virulent and deadly disease. The 2014 Ebola outbreak in West Africa was the largest in history. The rapid spread highlighted the need for a quick and accurate diagnostic method that can be employed in resource-limited conditions. In this study, we developed a probe that can be used as an internal positive control, coupled with a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay to accurately detect EBOV. This RT-LAMP assay is a simple one-step reaction performed at a constant temperature, and the results can be visualized by a colorimetric change from violet to sky blue. Our assay enabled detection of 10 copies of synthetic EBOV RNA within 1 hour. Compared to traditional RT-qPCR, RT-LAMP requires no sophisticated equipment, the results are easier to interpret, and they can be obtained in less time. These features make RT-LAMP an ideal method for detection of EBOV in low-resource settings.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 11, 2018

To investigate expression of the E3 ligase, RNF126, in human invasive breast cancer (BC) and i... more 1) To investigate expression of the E3 ligase, RNF126, in human invasive breast cancer (BC) and its links with BC outcomes. 2) To test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell cycle checkpoint kinase, CHK1. A retrospective analysis by immunohistochemistry (IHC) compared RNF126 staining in 110 invasive BC and 78 paired adjacent normal tissues with clinicopathologic data. Whether RNF126 controls CHK1 expression was determined by chromatin immunoprecipitation and a CHK1 promoter driven luciferase reporter. Staining for these two proteins by IHC using tissue microarrays was also conducted. Cell killing/replication stress induced by CHK1 inhibition was evaluated in cells, with or without RNF126 knockdown, by MTT/colony formation, replication stress biomarker immunostaining and DNA fiber assays. RNF126 protein expression was elevated in BC tissue samples. RNF126 was associated with a poor clinical outcome after multivariate analysis and was an in...

Molecular Endocrinology, Oct 1, 1992

Biology of Reproduction, Nov 1, 1997

The equine glycoprotein hormone a-subunit gene is expressed in both pituitary and placenta, unlik... more The equine glycoprotein hormone a-subunit gene is expressed in both pituitary and placenta, unlike that of all other nonprimate mammals studied, in which expression is limited to pituitary. Previous studies of the 5'-flanking region of the equine a-subunit promoter have revealed unique characteristics as well as similarities with the human a-subunit promoter, which demonstrates a similar pattern of tissue-specific expression. We have cloned and sequenced the equine a-subunit gene and have used tissue culture systems and transgenic mice to characterize its expression. Unlike the human promoter, the cloned equine et-subunit promoter failed to direct trophoblast-specific expression in either tissue culture or transgenic mouse models, suggesting an entirely different mechanism for expression. In contrast, the equine a-subunit promoter was able to direct gonadotroph expression in both tissue culture and transgenic mouse models. In aT3-1 cells, 550 base pair (bp) was sufficient for expression. This expression involves promoter elements identified in other species as playing a role in gonadotroph expression, but mutation of these elements reveals differences in their relative contributions to promoter activity. In mice, 2800 bp of 5'-flanking sequence allowed specific expression in gonadotrophs but not in thyrotrophs or placenta. The pattern of estrogen regulation observed in transgenic mice matched neither the repression that has been observed with human and bovine a-subunit promoters in transgenic mice nor the stimulation in mRNA levels reported in mares, suggesting a unique mechanism that is not recapitulated in the transgenic model. Thus the equine a-subunit promoter uses a combination of conserved and unique features of gene regulation to direct its pattern of tissue-specific expression.

Nature Genetics, Feb 8, 2021

Technological and computational advances in genomics and interactomics have made it possible to i... more Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein-protein interaction (PPI) networks within human cells. Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy subjects from the 1000 Genomes and ExAC projects. Somatic missense mutations are also significantly enriched in PPI interfaces compared to non-interfaces in 10,861 tumor exomes. We computationally identified 470 putative oncoPPIs in a pan-cancer analysis and demonstrate that the oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. We experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of them on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritizing alleles with PPI perturbing mutations to inform pathobiological mechanism and genotype-based therapeutic discovery.

Kaplan-Meier plot demonstrating that ESR1 expression predicts recurrence-free survival similarly ... more Kaplan-Meier plot demonstrating that ESR1 expression predicts recurrence-free survival similarly to FST in a cohort of over 2800 patients with breast cancer (all subtypes). Patients are stratified in high- and low-expressing groups for ESR1 using optimal cutoffs in the KM Plotter data analysis tool [58]. (PPTX 84 kb)

Follistatin inhibits activin A-induced invasion without impacting proliferation. a MCF10A and 4 T... more Follistatin inhibits activin A-induced invasion without impacting proliferation. a MCF10A and 4 T1 cells were treated with vehicle, recombinant human activin A (100 ng/ml), or activin A plus recombinant human FST (400 ng/ml), and cell number was assessed by MTS assay after 72 h. b MCF10A cells that overexpress rat c-Neu (10ANeu) were treated with vehicle, activin A (100 ng/ml), or activin A plus FST (400 ng/ml) for 48 h and plated for invasion assays in modified Boyden chambers + Matrigel overnight with serum as a chemoattractant in addition to follistatin and/or activin A (*p

FST expression is reduced in breast cancer cell lines compared with nontransformed mammary epithe... more FST expression is reduced in breast cancer cell lines compared with nontransformed mammary epithelial cells. a Western blot analysis of breast cancer cell lines demonstrating loss of FST expression compared with nontransformed (NT) mammary epithelial cells. b FST expression in MCF10A versus MCF10A-Neu stable cell lines that overexpress rat c-Neu/ErbB2 [27]. FST was assessed by quantitative RT-PCR relative to TATA-binding protein (TBP) mRNA (**pâ

Supplementary methods. (DOCX 21 kb)

FST overexpression in mouse mammary epithelia. a Follistatin-like 3 (Fstl3) is downregulated in H... more FST overexpression in mouse mammary epithelia. a Follistatin-like 3 (Fstl3) is downregulated in HER 2/Neu-induced mouse mammary tumors compared with normal mammary glands. Fstl3 expression in mammary glands and HER 2/Neu tumors was determined using data from a published microarray study of these tumors (*p

FST expression is associated with overall survival and metastasis in multiple cohorts of patients... more FST expression is associated with overall survival and metastasis in multiple cohorts of patients with breast cancer. Tumors are stratified into the highest 10% and lowest (remaining 90%) FST-expressing groups for each dataset as follows: Curtis et al. [54] reported FST low (n = 1774), FST high (n = 197); Hatzis et al. [53] reported FST low (n = 457), FST high (n = 51); and Kao et al. [55] reported FST low (n = 294), FST high (n = 33). FST expression does not predict recurrence to bone in the Bos et al. cohort [24]: FST low (n = 149), FST high (n = 17). (PPTX 109 kb)

Journal of Biological Chemistry, 2020

The phenotypes of each breast cancer subtype are defined by their transcriptomes. However, the tr... more The phenotypes of each breast cancer subtype are defined by their transcriptomes. However, the transcription factors that regulate differential patterns of gene expression that contribute to specific disease outcomes are not well understood. Here, using gene silencing and overexpression approaches, RNA-Seq, and splicing analysis, we report that the transcription factor B-cell leukemia/lymphoma 11A (BCL11A) is highly expressed in triple-negative breast cancer (TNBC) and drives metastatic disease. Moreover, BCL11A promotes cancer cell invasion by suppressing the expression of muscleblind-like splicing regulator 1 (MBNL1), a splicing regulator that suppresses metastasis. This ultimately increases the levels of an alternatively spliced isoform of integrin-α6 (ITGA6), which is associated with worse patient outcomes. These results suggest that BCL11A sustains TNBC cell invasion and metastatic growth by repressing MBNL1-directed splicing of ITGA6. Our findings also indicate that BCL11A lies at the interface of transcription and splicing and promotes aggressive TNBC phenotypes.

Glioblastoma (GBM) remains refractory to treatment. In addition to its cellular and molecular het... more Glioblastoma (GBM) remains refractory to treatment. In addition to its cellular and molecular heterogeneity, epidemiological studies indicate the presence of additional complexity associated with biological sex. GBM is more prevalent and aggressive in male compared to female patients, suggesting the existence of sex-specific growth, invasion, and therapeutic resistance mechanisms. While sex-specific molecular mechanisms have been reported at a tumor cell-intrinsic level, sex-specific differences in the tumor microenvironment have not been investigated. Using transgenic mouse models, we demonstrate that deficiency of junctional adhesion molecule-A (JAM-A) in female mice enhances microglia activation, GBM cell proliferation, and tumor growth. Mechanistically, JAM-A suppresses anti-inflammatory/pro-tumorigenic gene activation via interferon-activated gene 202b (Ifi202b) and found in inflammatory zone (Fizz1) in female microglia. Our findings suggest that cell adhesion mechanisms functi...

Molecular Endocrinology, 1991

LH, FSH, and TSH are heterodimeric glycoprotein hormones composed of a common a-subunit and uniqu... more LH, FSH, and TSH are heterodimeric glycoprotein hormones composed of a common a-subunit and unique 0-subunits. The a-subunit is produced in two distinct specialized cell types of the pituitary gland: gonadotropes, which synthesize LH and FSH, and thyrotropes, which synthesize TSH. We have demonstrated that 313 base pairs of the bovine-a subunit promoter direct expression of diphtheria toxin A chain specifically to the gonadotropes in transgenic mice. Animals carrying this transgene generally exhibit reproductive failure and lack of gonadal differentiation, consistent with gonadotrope ablation. Lack of gonadotrope activity was verified by RIA and immunohistochemical staining for LH. The phenotype of these transgenic mice is nearly identical to mice homozygous for the spontaneous mutation, hpg, which is due to a deletion in the gene encoding GnRH. Thyrotrope function was judged normal based on overall growth of the animals, appearance of their thyroids, T 4 levels measured by RIA, and immunohistochemical staining for TSH. The ablation of gonadotropes but not thyrotropes suggests that separate c/s-acting elements are necessary for expression of the a-subunit gene in these two cell types. Pituitary content of ACTH and GH was apparently normal, while PRL synthesis and storage were reduced. Thus, in a pituitary almost completely devoid of gonadotropes, most other pituitary functions were normal. This suggests that most pituitary cells are able to differentiate independently of terminal

Annals of the New York Academy of Sciences, 1989

The 18-bp direct repeat occurring between positions -146 and -111 in the 5&amp;#39;-flank... more The 18-bp direct repeat occurring between positions -146 and -111 in the 5&amp;#39;-flanking region of the human alpha-subunit gene serves two functions: it mediates the transcriptional effect of cAMP and it acts in conjunction with an adjacent cis-acting element (URE) to confer properties of placental-specific expression to the alpha-subunit promoter. Functional activity of the URE and CRE requires binding of a trans-acting factor; each element binds a different factor. Analysis of saturation isotherms provides good evidence that cooperativity is involved in binding of CREB to the 18-bp direct repeat. This cooperativity could account for the synergistic effect of two CRE on both basal and cAMP-stimulated transcription. It remains to be determined whether heterotropic cooperativity is involved in binding of trans-acting factors to the URE and CRE. A major difference between the 5&amp;#39;-flanking region of the human alpha-subunit gene and comparable regions from bovine, rat, and mouse alpha-subunit genes is that the latter contain a single CRE homolog which appears incapable of binding the trans-acting factor that binds to the human alpha CRE. Lack of a functional CRE provides at least one explanation for inactivity of the bovine alpha-subunit promoter in choriocarcinoma cells and probably in bovine placenta as well. Yet, the same bovine promoter-regulatory region that lacks a functional CRE is capable of conferring pituitary-specific expression to the CAT gene in transgenic mice (data not shown). This suggests that the CRE is not required for pituitary-specific expression of the bovine alpha-subunit gene. Instead, another cis-acting element(s) must confer this property to the alpha-subunit promoter. While it is tempting to suggest that bovine, rat, and mouse alpha-subunit genes are not regulated by cAMP because of their inactive CRE homolog, it is also quite possible that other CRE are located further upstream. Accordingly, it will be of interest to obtain additional 5&amp;#39;-flanking sequence and determine whether functional homologs of the human alpha CRE are present in the bovine, rat, and mouse alpha-subunit genes, or whether another class of cis-acting elements provide cAMP-responsiveness.

Pharmacological research, 2018

Breast cancer is a collection of distinct tumor subtypes that are driven by unique gene expressio... more Breast cancer is a collection of distinct tumor subtypes that are driven by unique gene expression profiles. These transcriptomes are controlled by various epigenetic marks that dictate which genes are expressed and suppressed. During carcinogenesis, extensive restructuring of the epigenome occurs, including aberrant acetylation, alteration of methylation patterns, and accumulation of epigenetic readers at oncogenes. As epigenetic alterations are reversible, epigenome-modulating drugs could provide a mechanism to silence numerous oncogenes simultaneously. Here, we review the impact of inhibitors of the Bromodomain and Extraterminal (BET) family of epigenetic readers in breast cancer. These agents, including the prototypical BET inhibitor JQ1, have been shown to suppress a variety of oncogenic pathways while inducing minimal, if any, toxicity in models of several subtypes of breast cancer. BET inhibitors also synergize with multiple approved anti-cancer drugs, providing a greater res...

F1000 - Post-publication peer review of the biomedical literature, 2012

Purpose-Anticancer drug development is inefficient, but genetically engineered murine models (GEM... more Purpose-Anticancer drug development is inefficient, but genetically engineered murine models (GEMM) and orthotopic, syngeneic transplants (OST) of cancer may offer advantages to in vitro and xenograft systems.

Cancers

The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast c... more The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast cancer. Everolimus is an mTORC1 inhibitor used in metastatic estrogen receptor-positive (ER+) and epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, mTORC1 inhibitors have limited efficacy in other breast cancer subtypes. We sought to discover collateral sensitivities to mTORC1 inhibition that could be exploited to improve therapeutic response. Using a mouse model of breast cancer that is intrinsically resistant to mTORC1 inhibition, we found that rapamycin alters the expression of numerous extracellular matrix genes, suggesting a potential role for integrins/FAK in controlling mTORC1-inhibitor efficacy. FAK activation was also inversely correlated with rapamycin response in breast cancer cell lines. Supporting its potential utility in patients, FAK activation was observed in >50% of human breast cancers. While blocking FAK in mouse models of breast cancer that...

Cancers, 2021

The pioneering function of FOXA1 establishes estrogen-responsive transcriptomes in luminal breast... more The pioneering function of FOXA1 establishes estrogen-responsive transcriptomes in luminal breast cancer. Dysregulated FOXA1 chromatin occupancy through focal amplification, mutation, or cofactor recruitment modulates estrogen receptor (ER) transcriptional programs and drives endocrine-resistant disease. However, ER is not the sole nuclear receptor (NR) expressed in breast cancers, nor is it the only NR for which FOXA1 serves as a licensing factor. Receptors for androgens, glucocorticoids, and progesterone are also found in the majority of breast cancers, and their functions are also impacted by FOXA1. These NRs interface with ER transcriptional programs and, depending on their activation level, can reprogram FOXA1-ER cistromes. Thus, NR interplay contributes to endocrine therapy response and resistance and may provide a vulnerability for future therapeutic benefit in patients. Herein, we review what is known regarding FOXA1 regulation of NR function in breast cancer in the context ...