Mammary Cell News Volume 10.19 | May 17 2018

TOP STORY

KLHL22 Activates Amino-Acid-Dependent mTORC1 Signaling to Promote Tumorigenesis and Aging

Researchers found that in response to amino acids, the CUL3-KLHL22 E3 ubiquitin ligase promoted K48-linked polyubiquitination and degradation of DEPDC5, an essential subunit of GATOR1. [Nature] Abstract

(Ranked by impact factor of the journal)

Notch Ligand Dll1 Mediates Cross-Talk between Mammary Stem Cells and the Macrophageal Niche

Scientists showed that Dll1, a Notch pathway ligand, was enriched in mammary gland stem cells (MaSCs) and mediated critical interactions with stromal macrophages in the surrounding niche. Conditional deletion of Dll1 reduced the number of MaSCs and impaired ductal morphogenesis in the mammary gland. [Science] Abstract | Press Release

Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade

Investigators described an unbiased phenotypic combinatorial screening approach to identify a bispecific immunoglobulin G1 (IgG1) antibody against HER2 and HER3. In tumor models resistant to HER2-targeting agents, the bispecific IgG1 potently inhibited the heregulin/HER3 pathway and downstream phosphatidylinositide-3 kinase/Akt signaling via a “dock & block” mechanism. [Cancer Cell] Abstract | Graphical Abstract | Press Release

STT3-Dependent PD-L1 Accumulation on Cancer Stem Cells Promotes Immune Evasion

The authors demonstrated that epithelial-mesenchymal transition (EMT) enriched PD-L1 in cancer stem-like cells by the EMT/β-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induced N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilized and upregulated PD-L1. [Nat Commun] Full Article

Genome-Wide and High-Density CRISPR-Cas9 Screens Identify Point Mutations in PARP1 Causing PARP Inhibitor Resistance

Researchers identified close to full-length mutant forms of PARP1 that cause in vitro and in vivo PARP inhibitor (PARPi) resistance. Mutations both within and outside of the PARP1 DNA-binding zinc-finger domains caused PARPi resistance and altered PARP1 trapping, as did a PARP1 mutation found in a clinical case of PARPi resistance. [Nat Commun] Full Article | Press Release

The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells

Loss of members of the CTC1-STN1-TEN1 (CST) complex were found to cause poly(ADP-ribose) polymerase inhibitor resistance in BRCA1-deficient cells in vitro and in vivo. Scientists showed that CTC1 depletion results in the restoration of end resection and that the CST complex may act downstream of 53BP1/RIF1. [Cell Rep] Full Article | Graphical Abstract

Defective Replication Stress Response Is Inherently Linked to the Cancer Stem Cell Phenotype

Investigators found that replication stress response defects rewired non-malignant cells into a cancer stem cell (CSC)-like state, and analysis of CSCs indicated that they inherently harbor replication stress response defects. They also identified a dependence on MEK/ERK signaling. Inhibition of this signaling cascade restored oncogene-induced senescence through a p53-independent MDM2/p21 axis. [Cell Rep] Full Article | Graphical Abstract

KMT2C Mediates the Estrogen Dependence of Breast Cancer through Regulation of ERα Enhancer Function

The authors identified the H3K4 methyltransferase KMT2C as necessary for hormone-driven estrogen receptor alpha (ERα) activity and breast cancer proliferation. KMT2C knockdown suppressed estrogen-dependent gene expression and caused H3K4me1 and H3K27ac loss selectively as ERα enhancers. [Oncogene] Full Article

LncRNA PVT1 Regulates Triple-Negative Breast Cancer through KLF5/Beta-Catenin Signaling

Researchers found that PVT1 depletion inhibited cell proliferation, colony formation, and orthotopic xenograft tumor growth. PVT1 bound with KLF5 and increased its stability via BAP1, which upregulated beta-catenin signaling, resulting in enhanced triple-negative breast cancer tumorigenesis. [Oncogene] Abstract

A Novel Long Non-Coding RNA-PRLB Acts as a Tumor Promoter through Regulating miR-4766-5p/SIRT1 Axis in Breast Cancer

Scientists demonstrated that progression-associated lncRNA (lncRNA-PRLB) in breast cancer was upregulated in human breast cancer tissues and breast cancer cell lines. LncRNA-PRLB positively correlated with the extent of metastasis, and its expression correlated with shorter survival time of breast cancer patients. [Cell Death Dis] Full Article

Antitumor Effect of Axitinib Combined with Dopamine and PK-PD Modeling in the Treatment of Human Breast Cancer Xenograft

Investigators showed that axitinib up-regulated the expression of breast cancer stem-like cell (BCSC) markers (CD44⁺/CD24^−/low) in vivo, and dopamine significantly synergized the inhibitory effect on tumor growth by deducting the BCSC frequency. [Acta Pharmacol Sin] Abstract

Targeting MUC1-C Suppresses BCL2A1 in Triple-Negative Breast Cancer

MUC1-C activated the B-cell lymphoma 2-related protein A1 (BCL2A1) gene by an NF-κB p65-mediated mechanism, linking this pathway with the induction of epithelial-mesenchymal transition. The authors found that inhibiting MCL-1 with the highly specific MS1 peptide results in the activation of the MUC1-C→NF-κB→BCL2A1 pathway. [Signal Transduct Target Ther] Full Article

Homologous Recombination Deficiency and Host Anti-Tumor Immunity in Triple-Negative Breast Cancer

Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in triple-negative breast cancer (TNBC) offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. [Breast Cancer Res Treat] Full Article

Applications of RNA Indexes for Precision Oncology in Breast Cancer

Scientists take breast cancer as an example to demonstrate the applications of RNA resources in precision medicine exploration. These include the use of mRNA profiles in triple-negative breast cancer subtyping to inform corresponding candidate targeted therapies; current advancements and achievements of high-throughput RNA interference screening techniques in breast cancer; and microRNAs as functional signatures for defining cell identities and regulating the biological activities of breast cancer cells. [Genomics Proteomics Bioinformatics] Full Article

Visit our reviews page to see a complete list of reviews in the mammary cell research field.

Six Months of Breast Cancer Treatment ‘Could Be as Effective as 12’ in Some Women with Early Stage Disease

Six months of targeted treatment could be as effective as 12 months for women with a type of early stage breast cancer, according to unpublished clinical trial results. All the women taking part in the study had HER2-positive breast cancer, which means their cancer cells can be targeted by Herceptin. [Press release from Cancer Research UK discussing research to be presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago] Press Release

Daiichi Sankyo to Present New Data on Multiple Compounds Including Antibody Drug Conjugates DS-8201 and U3-1402

Daiichi Sankyo Company, announced that it will present new data for multiple investigational compounds in the Daiichi Sankyo Cancer Enterprise pipeline. [Press release from Daiichi Sankyo, Inc. discussing research to be presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago] Press Release

MEI Pharma to Present Clinical Data

Study investigators will present updated results from the Phase Ib study evaluating ME-401 in relapsed/refractory indolent B-cell malignancies and from an investigator-initiated study of ME-344 in patients with HER2-negative breast cancer. [Press release from MEI Pharma Inc., discussing research to be presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago] Press Release

Cancer Treatment Developed at Ben-Gurion University Shows Ability to Reprogram Cancer Cells to Pre-Cancerous State

BGN Technologies, and the NIBN announced that a research group led by Prof. Varda Shoshan-Barmatz, the Department of Life Sciences, and the National Institute for Biotechnology at Ben-Gurion University is developing a novel molecule for the treatment of cancer, which has shown not only inhibition of growth of cancer cells, but also the ability to reprogram the cancer cells back to normal-like cells. [BGN Technologies Ltd.] Press Release

Rosalind Franklin University Breaks Ground on New Science Park

The research park, which will be built on the university’s campus in Lake County, home to the largest concentration of bioscience companies in the Midwest, will offer a collaborative environment for academic and industry scientists, innovators and entrepreneurs, with the goal of accelerating Rosalind Franklin University’s nationally recognized research into treatment and prevention of disease. [Rosalind Franklin University] Press Release

Huge Gender Disparity in Cancer Research Funding in U.K.

The analysis examined data on both public and philanthropic grants given to support cancer research in the U.K. Male PIs were awarded 69 percent of the grants, and their grants were on average 1.3 times as large as those given to women, so that they received 78 percent of the total money allocated. [The Scientist] Editorial

Patient Registries to Bolster Cell- and Gene-Therapy Clinical Trial Data

As the first personalized cell and gene therapies are approved from small clinical trials, researchers propose the creation of publicly accessible databases to pull together real-world results. [The Scientist] Editorial

NIH’s Plum Award for Young Scientists Skews Male, Agency’s Data Show

These prestigious grants aim to vault the most promising new Ph.D.s to independence by allowing them to bypass postdoctoral fellowships and start their own labs immediately, providing up to $250,000 annually for 5 years. But since the awards were launched by NIH Director Francis Collins in 2010, men have consistently won them in numbers exceeding their representation in the applicant pool. [ScienceInsider] Editorial

Sacked Japanese Biologist Gets Chance to Retrain at Crick Institute

Prominent cell biologist Yoshinori Watanabe, who was dismissed by the University of Tokyo last month, is attempting to put his past behind him by embarking on an intensive retraining program with Nobel prizewinner Paul Nurse in London. The university dismissed Watanabe after an investigation concluded that he had committed scientific misconduct. [Nature News] Editorial

Europe’s Open-Access Drive Escalates As University Stand-Offs Spread

Bold efforts to push academic publishing towards an open-access model are gaining steam. Negotiators from libraries and university consortia across Europe are sharing tactics on how to broker new kinds of contracts that could see more articles appear outside paywalls. [Nature News] Editorial

Sweden Cancels Agreement with Elsevier over Open Access

A collection of Swedish universities and research institutions will not renew its current contract with Elsevier that expires at the end of June, Times Higher Education reports. The move comes not long after academic institutions in other countries have let publishers’ subscriptions lapse when fee negotiations come to an impasse. [The Scientist] Editorial

NEW Making It Personal: Cancer Precision Medicine
November 5-7, 2018
Bergamo, Italy

Visit our events page to see a complete list of events in the community.

NEW Postdoctoral Posion – Basic & Translational Breast Cancer Research (Northwestern University)

NEW Researcher Positions – Genome Directed Cancer Therapy (University of Bergen)

NEW Postdoctoral Position – Genome Directed Cancer Therapy (University of Bergen)

Postdoctoral Positions – Translational Bioinformatics or Molecular Cancer Biology (University of Pittsburgh Cancer Institute)

Postdoctoral Research Fellow – Translational Mitochondrial Research (Fred Hutch Cancer Research Center)

Postdoctoral Position – Breast Cancer Research (Rutgers Cancer Institute of New Jersey)

Graduate Student – Breast and Colorectal Cancer (Dalhousie University)

Postdoctoral Fellows – Breast Cancer Stem Cell Research (New York University School of Medicine)

Postdoctoral Fellow or Research Scientist – Breast Cancer Research (Icahn School of Medicine at Mount Sinai)

Postdoctoral Fellowship – Cancer Research (Mass General Hospital/Harvard Medical School)

Postdoctoral Fellow – Breast Cancer Research (Northwestern University)

Postdoctoral Researcher – Breast Cancer (Baylor College of Medicine)

Senior Research Technician – Breast Cancer (Baylor College of Medicine)

Research Technician – Breast Cancer (Baylor College of Medicine)

Postdoctoral Fellow – Cancer Research (Indiana Uniersity School of Medicine)

Postdoctoral Fellows – Molecular and Translational Cancer Biology (Thomas Jefferson University)

Postdoctoral Researcher – Breast Cancer (UT Southwestern Medical Center)

Staff Position – Breast Cancer Tumor Immunology (Cleveland Clinic Taussig Cancer Institute)

Research Fellow – Breast Cancer (Dana-Farber Cancer Institute)

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