Mammary Cell News Volume 9.21 | Jun 1 2017

TOP STORY

Study Identifies RNA Molecule that Shields Breast Cancer Stem Cells from Immune System

Researchers have identified a small RNA molecule that helps maintain the activity of stem cells in both healthy and cancerous breast tissue. The study suggests that this “microRNA” promotes particularly deadly forms of breast cancer and that inhibiting the effects of this molecule could improve the efficacy of existing breast cancer therapies. [Press release from Princeton University discussing online prepublication in Nature Cell Biology] Press Release | Abstract | Blog Post

(Ranked by impact factor of the journal)

LABORATORY RESEARCH

A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability

In cells bearing heterozygous mutations, the authors found that a cellular metabolite and ubiquitous environmental toxin, formaldehyde, stalls and destabilizes DNA replication forks, engendering structural chromosomal aberrations. Formaldehyde selectively depleted BRCA2 via proteasomal degradation, a mechanism of toxicity that affects very few additional cellular proteins. [Cell] Full Article | Press Release | Graphical Abstract

The Brain Microenvironment Mediates Resistance in Luminal Breast Cancer to PI3K Inhibition through HER3 Activation

Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these microenvironments, scientists observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. [Sci Transl Med] Full Article | Press Release

A-Kinase Anchoring Protein BIG3 Coordinates Estrogen Signaling in Breast Cancer Cells

Researchers demonstrated that brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) functions as an A-kinase anchoring protein that binds protein kinase A (PKA) and the α isoform of the catalytic subunit of protein phosphatase 1 (PP1Cα), thereby dephosphorylating and inactivating PHB2. E2-induced PKA-mediated phosphorylation of BIG3-S305 and -S1208 served to enhance PP1Cα activity, resulting in E2/ERα signaling activation via prohibitin 2 (PHB2) inactivation due to PHB2-S39 dephosphorylation. [Nat Commun] Full Article

Frizzled7 Antibody-Functionalized Nanoshells Enable Multivalent Binding for Wnt Signaling Inhibition in Triple Negative Breast Cancer Cells

Research has shown that antibodies conjugated to nanoparticles display increased affinity for their target relative to freely delivered antibodies due to multivalency, and the authors investigated how this multivalency could enable antibody–nanoparticle conjugates to inhibit oncogenic cell signaling more effectively than freely delivered antibodies. This effect was evaluated using triple negative breast cancer cells that are characterized by hyperactive Wnt signaling mediated through overexpressed Frizzled7 transmembrane receptors. [Small] Abstract

BPTF Maintains Chromatin Accessibility and the Self-Renewal Capacity of Mammary Gland Stem Cells

Scientists showed that BPTF, the largest subunit of the NURF chromatin remodeling complex, is essential for mammary stem cell self-renewal and differentiation of mammary epithelial cells. BPTF depletion arrested cells at a previously undefined stage of epithelial differentiation that is associated with an incapacity to achieve the luminal cell fate. [Stem Cell Reports] Full Article | Press Release | Graphical Abstract

SK4 Channels Modulate Ca²⁺-Signaling and Cell Cycle Progression in Murine Breast Cancer

Investigators generated SK4-negative tumors by crossing SK4-deficient mice to the polyoma middle T-antigen (PyMT) and epidermal growth factor receptor 2 breast cancer models in which oncogene expression is driven by the retroviral promotor MMTV. Ablation of SK4 and TRAM-34 treatment reduced the SK4-generated current fraction, growth factor-dependent Ca²⁺ entry, cell cycle progression and the proliferation rate of MMTV-PyMT tumor cells. [Mol Oncol] Abstract | Full Article

Mutation Site and Context Dependent Effects of ESR1 Mutation in Genome-Edited Breast Cancer Cell Models

Researchers describe the generation and characterization of genome-edited T47D and MCF7 breast cancer cell lines with the two most common estrogen receptor alpha 1 gene (ESR1) mutations, Y537S and D538G. Cells with ESR1 mutations displayed ligand-independent estrogen receptor (ER) activity, and were resistant to several selective ER modulators and degraders, with cell line and mutation-specific differences with respect to magnitude of effect. [Breast Cancer Res] Full Article

TRPC1 Is a Differential Regulator of Hypoxia-Mediated Events and Akt Signaling in PTEN-Deficient Breast Cancer Cells

Investigators identified the transient receptor potential canonical-1 (TRPC1) ion channel as a key component of responses to hypoxia in breast cancer cells. This regulation included control of specific epithelial to mesenchymal transition events and hypoxia–mediated activation of signaling pathways such as activation of the EGFR, STAT3 and the autophagy marker LC3B, through hypoxia-inducible factor-1-alpha-dependent and -independent mechanisms. [J Cell Sci] Abstract

CLINICAL RESEARCH

Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy

The authors randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy to receive standard postsurgical treatment either with capecitabine or without. After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. [N Engl J Med] Abstract

Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2 Negative Metastatic Breast Cancer (MBC)

Investigators examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on breast cancer stem cells in MBC patients. There were neither G4-5 adverse events nor serious adverse events related to study therapy, and no interactions between reparixin and paclitaxel to influence their respective PK profiles. Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. [Clin Cancer Res] Abstract

Clinical Utility of Gene-Expression Signatures in Early Stage Breast Cancer

The authors describe the available data on the clinical validity of the most widely available assays in patients with early stage breast cancer, with a focus on the development, validation, and clinical application of these assays, in addition to the anticipated outcomes of ongoing prospective trials. They also review data from comparative studies of these assays and from cost-effectiveness analyses relating to their clinical use. [Nat Rev Clin Oncol] Abstract

Prolactin Receptor Targeting in Breast and Prostate Cancers: New Insights into an Old Challenge

Preclinical investigations, epidemiological studies and analyses of tissue specimens from patients strongly support the contribution of prolactin receptor (PRLR) signaling to breast and prostate tumorigenesis and cancer progression. Nevertheless, the PRLR neutralizing antibody LFA102 tested recently in a Phase I trial in advanced, PRLR-positive prostate cancer and breast cancer patients failed to provide any clinical benefit. This underlines the need to better understand the actual impact of PRLR signaling on the progression of these cancers. [Pharmacol Ther] Abstract

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

Abramson Cancer Center Studies Show Hope for Multiple Cancers with Pembrolizumab Combination Therapies

The combination of pembrolizumab and the checkpoint inhibitor known as epacadostat is leading to promising responses and is generally well tolerated in patients with triple-negative breast cancer, non-small cell lung cancer, squamous cell cancer of the head and neck, and several other cancers, according to researchers. Their findings also showed that adding pembrolizumab to standard therapies for breast cancer improved the number of patients achieving a pathological complete response. [Press release from Penn Medicine discussing research to be presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago] Press Release

OHSU Knight Cancer Institute Selected to Join Prestigious National Consortium, Receive $9.2 Million

The National Cancer Institute (NCI) has awarded a research team at the Oregon Health & Science University (OHSU) Knight Cancer Institute $9.2 million over five years to serve as a research center in the NCI’s Cancer Systems Biology Consortium. The project aims to develop strategies for improving treatment-resistant triple negative breast cancer, an aggressive form of breast cancer that lacks key receptors known to fuel most breast cancers: estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2. [Oregon Health & Science University] Press Release

Latest Grant Awards Bring More than $6 Million to Roswell Park Research Projects

Researchers at Roswell Park Cancer Institute have garnered $6.4 million in new grant funding to support important investigations. This includes a two-year, $360,000 Peter T. Rowley Breast Cancer Project grant to Sharon Evans, PhD, Professor of Oncology and Immunology in the Department of Immunology, funded by the New York State Department of Health to investigate mechanisms that lead to immunotherapy treatment failure in aggressive breast cancer. [Roswell Park Cancer Institute] Press Release

Trials of Embryonic Stem Cells to Launch in China

The first clinical trial in China using human embryonic stem (ES) cells, and the first one worldwide aimed at treating Parkinson’s disease using ES cells from fertilized embryos, will begin in the next few months. In a second trial starting around the same time, a different team in Zhengzhou will use ES cells to target vision loss caused by age-related macular degeneration. [Nature News] Editorial

Web of Science Owner Buys up Booming Peer-Review Platform

The owner of the vast science-citation database Web of Science — Clarivate Analytics — is buying up a firm that has gathered hundreds of thousands of peer-review records, in a deal that could lead to new ways of organizing scientific peer review and preventing peer-review fraud. [Nature News] Editorial

Pay-to-View Blacklist of Predatory Journals Set to Launch

Five months after a widely read blog listing possible ‘predatory’ scholarly journals and publishers was shut down, another index of untrustworthy titles is appearing — although this version will be available only to paying subscribers. [Nature News] Editorial

NIH Finds Using Anonymous Proposals to Test for Bias Is Harder than It Looks

An effort to test whether reviewers are biased against blacks applying for grants from the National Institutes of Health (NIH) is proving to be much harder to carry out than expected. [ScienceInsider] Editorial

NEW Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond
September 24-27, 2017
Orlando, United States

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

NEW Postdoctoral Training Fellow – Breast Cancer (Institute of Cancer Research)

NEW Postdoctoral Research Associate – Breast Cancer (University of Nebraska Medical Center)

NEW Research Position – Translational Breast Cancer Research (Northwestern University)

Postdoctoral Training Fellow – Cancer Metabolism (The Francis Crick Institute)

Postdoctoral Fellow – Metastatic Breast Cancer Stem Cells (Memorial Sloan-Kettering Cancer Center)

Statistical Bioinformatician – Breast Cancer Research (Institute of Cancer Research)

Postdoctoral Researcher Positions – Fundamental Mechanisms of Tyrosine Kinase Mediated Epigenetic Modifications (Moffitt Comprehensive Cancer Center)

Postdoctoral Positions – Cancer Research (Baylor College of Medicine)

Researcher – Tumor Microenvironment and Invasion Program (SUNY Upstate Medical University)

Postdoctoral Fellow Position(s) – Gene Regulation in Cancer Progression (University of Texas Health Science Center at San Antonio)

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