Mammary Cell News Volume 9.07 | Feb 23 2017

TOP STORY

CX-5461 Is a DNA G-Quadruplex Stabilizer with Selective Lethality in BRCA1/2 Deficient Tumors

Researchers showed that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumors resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocked replication forks and induced ssDNA gaps or breaks. [Nat Commun] Full Article

(Ranked by impact factor of the journal)

LABORATORY RESEARCH

A Class of Extracellular Vesicles from Breast Cancer Cells Activates VEGF Receptors and Tumor Angiogenesis

The authors describe how a specific class of extracellular vesicles, called microvesicles (MVs), activated VEGF receptors and tumor angiogenesis through a unique 90 kDa form of VEGF (VEGF_90K). They showed that VEGF_90K is generated by the crosslinking of VEGF₁₆₅, catalyzed by the enzyme tissue transglutaminase, and associated with MVs through its interaction with the chaperone Hsp90. [Nat Commun] Full Article

Cancer Stem Cells Regulate Cancer-Associated Fibroblasts via Activation of Hedgehog Signaling in Mammary Gland Tumors

Scientists investigated the interactions between cancer stem cells (CSCs) and cancer associated fibroblasts (CAFs) in mammary gland tumors driven by combined activation of Wnt/β-catenin and Hgf/Met signaling in mouse mammary epithelial cells. In this setting, CSCs secreted the hedgehog ligand SHH, which regulated CAFs via paracrine activation of Hedgehog signaling. [Cancer Res] Abstract

Evolution of Cancer Stem-Like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles

The hypothesis that microvesicle (MV)-mediated microRNA transfer converts non-cancer stem cells into cancer stem cells leading to therapy resistance remains poorly investigated. Investigators provide direct evidence supporting this hypothesis, by demonstrating how MV derived from cancer associated fibroblasts transfer miR-221 to promote hormonal therapy resistance in models of luminal breast cancer. [Cancer Res] Abstract

Retinoic Acid Directs Breast Cancer Cell State Changes through Regulation of TET2-PKCζ Pathway

Scientists provide evidence showing that all-trans retinoic acid (ATRA) induces the interaction and chromatin recruitment of a novel RARβ-TET2 complex to epigenetically activate a specific cohort of gene targets, including MiR-200c. Their data revealed that pharmacological concentration of ATRA effectively downregulates PKCζ through activation of miR-200c, leading to a decrease of the stem cell-like populations from non-tumorigenic mammary epithelial cells and non-aggressive breast cancer cells. [Oncogene] Full Article

Chemotherapy-Induced Ca²⁺ Release Stimulates Breast Cancer Stem Cell Enrichment

The authors found that chemotherapy induces the expression of glutathione S-transferase omega 1 (GSTO1), which is dependent on hypoxia-inducible factor (HIF)-1 and HIF-2. Knockdown of GSTO1 expression abrogated carboplatin-induced breast cancer stem cells enrichment, decreased tumor initiation and metastatic capacity, and delayed tumor recurrence after chemotherapy. [Cell Rep] Full Article | Press Release | Graphical Abstract

Pentraxin-3 Is a PI3K Signaling Target that Promotes Stem Cell-Like Traits in Basal-Like Breast Cancers

Using transcriptomic analysis of activated PIK3CA–expressing basal-like breast cancers cells, investigators identified the gene encoding the humoral pattern recognition molecule pentraxin-3 as a critical target of oncogenic phosphoinositide 3-kinase (PI3K) signaling. [Sci Signal] Abstract | Press Release | Podcast

HOXC8 Regulates Self-Renewal, Differentiation and Transformation of Breast Cancer Stem Cells

Scientists screened the expression of homeobox genes in mammary stem cells to establish their role in stem cell transformation in breast cancer. They demonstrated altered expression of homeobox genes in breast cancer stem/progenitor cells. HOXC8 was consistently downregulated in stem/progenitor cells of all breast molecular subtypes, thus representing a tumor suppressor candidate. [Mol Cancer] Full Article

POMC Maintains Tumor-Initiating Properties of Tumor Tissue-Derived Long-Term-Cultured Breast Cancer Stem Cells

Researchers generated two tumor tissue-derived breast cancer stem cell (BCSC) lines that showed prolonged maintenance over 20 serial passages in vitro, while retaining their tumor-initiating biological properties. They found that inhibition of pro-opiomelanocortin (POMC) attenuates phosphorylation of AKT2 and GSK3β in BCSC. [Int J Cancer] Abstract

Cellular Glycosylation Affects Herceptin Binding and Sensitivity of Breast Cancer Cells to Doxorubicin and Growth Factors

The authors investigated the effect of N-linked glycosylation on the binding of Herceptin to HER2 protein in breast cancer and on the sensitivity of cancer cells to the chemotherapeutic agent doxorubicin (DXR) and growth factors. Maintenance of SKBR-3 cells in tunicamycin resulted in an increase in sensitivity to DXR and a decrease in sensitivity to IGF-1 alone and to IGF-1 supplemented with EGF. [Sci Rep] Full Article

CLINICAL RESEARCH

Constitutional Variants Are Not Associated with HER2-Positive Breast Cancer: Results from the SIGNAL/PHARE Clinical Cohort

Scientists sought to identify variants specifically related to human epidermal growth factor receptor 2-positive breast cancer. Despite having 80% power to detect an odds ratio of 1.23 in the population, no variant achieved genome-wide significance for association with the occurrence of human epidermal growth factor receptor 2–positive breast cancer vs. any other subtype of breast tumor. [NPJ Breast Cancer] Full Article

From Basic Apoptosis Discoveries to Advanced Selective BCL-2 Family Inhibitors

The authors review the latest progress in direct and selective targeting of B cell lymphoma 2 (BCL-2) family proteins for cancer therapy. [Nat Rev Drug Discov] Abstract

PI3K-AKT-mTOR Inhibitors in Breast Cancers: From Tumor Cell Signaling to Clinical Trials

Scientists aim to understand the role of PI3K-mTORC1/C2 alterations in determining the clinical outcome in the specific breast cancer subtypes. [Pharmacol Ther] Abstract

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

Lynparza Meets Primary Endpoint in Phase III Trial in BRCA-Mutated Metastatic Breast Cancer

AstraZeneca announced positive results from its Phase III OLYMPIAD trial comparing Lynparza tablets to physician’s choice of a standard of care chemotherapy in the treatment of patients with HER2-negative metastatic breast cancer harboring germline BRCA1 or BRCA2 mutations. Patients treated with Lynparza showed a statistically-significant and clinically-meaningful improvement in progression-free survival compared with those who received chemotherapy. [AstraZeneca] Press Release

Incyte Announces Oncology Research Alliance with the Abramson Cancer Center at the University of Pennsylvania

Incyte Corporation announced a multi-year research collaboration with the Abramson Cancer Center at the University of Pennsylvania. Through this collaboration, Incyte and Abramson have agreed to bring together the knowledge and expertise of their leading drug discovery and development scientists to conduct collaborative research aimed at advancing the understanding of cancer biology and fostering innovative science in immunotherapy. [Incyte Corporation] Press Release

Updated: Will They or Won’t They? What Science Groups Are Saying About Joining the March for Science

The March for Science is creating a buzz in the scientific community. The march arose as a grassroots reaction to concerns about the conduct of science under President Donald Trump. And it has spurred debate over whether it will help boost public support for research, or make scientists look like another special-interest group, adding to political polarization. [ScienceInsider] Editorial

Updated: More Groups Sue to Force USDA to Restore Online Animal Welfare Records

The U.S. Department of Agriculture (USDA) restored some of the tens of thousands of animal welfare documents that it removed from its website early this month. [ScienceInsider] Editorial

NEW 2^nd Global Cancer Summit 2017
March 22-24, 2017
Kuala Lumpur, Malaysia

NEW IMPAKT 2017 Breast Cancer Conference
May 4-6, 2017
Brussels, Belgium

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

NEW Postdoctoral Fellow – Estrogen Receptor Positive Breast Cancer (AstraZeneca)

Senior Faculty Position – Epidemiology (Institute of Cancer Research)

Cancer Bioinformatician – Breast Cancer (Institute of Cancer Research)

Assistant or Associate Professor – Breast Cancer (Roswell Park Cancer Institute)

Postdoctoral Positions – Molecular Cancer Research (University of Copenhagen)

Postdoctoral Associate – Department of Therapeutic Radiology (Yale University School of Medicine)

Postdoc Positions – Molecular Cancer Biology and Bioinformatics (University of Pittsburgh)

Postdoctoral Fellow – Breast Cancer (University of Hawaii Cancer Center)

Postdoctoral Associate – Mammary Stem Cell and Cancer Biology (University of Miami)

Assistant Professor – Molecular Therapeutics of Cancer (Dartmouth College)

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