Editorial Board

Publication date: 15 August 2018
Source:Molecular and Cellular Endocrinology, Volume 471





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Integrated molecular analysis of Tamoxifen-resistant invasive lobular breast cancer cells identifies MAPK and GRM/mGluR signaling as therapeutic vulnerabilities

Publication date: 15 August 2018
Source:Molecular and Cellular Endocrinology, Volume 471
Author(s): Hillary Stires, Mary M. Heckler, Xiaoyong Fu, Zhao Li, Catherine S. Grasso, Michael J. Quist, Joseph A. Lewis, Uwe Klimach, Alan Zwart, Akanksha Mahajan, Balázs Győrffy, Luciane R. Cavalli, Rebecca B. Riggins
Invasive lobular breast cancer (ILC) is an understudied malignancy with distinct clinical, pathological, and molecular features that distinguish it from the more common invasive ductal carcinoma (IDC). Mounting evidence suggests that estrogen receptor-alpha positive (ER+) ILC has a poor response to Tamoxifen (TAM), but the mechanistic drivers of this are undefined. In the current work, we comprehensively characterize the SUM44/LCCTam ILC cell model system through integrated analysis of gene expression, copy number, and mutation, with the goal of identifying actionable alterations relevant to clinical ILC that can be co-targeted along with ER to improve treatment outcomes. We show that TAM has several distinct effects on the transcriptome of LCCTam cells, that this resistant cell model has acquired copy number alterations and mutations that impinge on MAPK and metabotropic glutamate receptor (GRM/mGluR) signaling networks, and that pharmacological inhibition of either improves or restores the growth-inhibitory actions of endocrine therapy.



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Fighting breast cancer stem cells through the immune-targeting of the xCT cystine–glutamate antiporter

Abstract

Tumor relapse and metastatic spreading act as major hindrances to achieve complete cure of breast cancer. Evidence suggests that cancer stem cells (CSC) would function as a reservoir for the local and distant recurrence of the disease, due to their resistance to radio- and chemotherapy and their ability to regenerate the tumor. Therefore, the identification of appropriate molecular targets expressed by CSC may be critical in the development of more effective therapies. Our studies focused on the identification of mammary CSC antigens and on the development of CSC-targeting vaccines. We compared the transcriptional profile of CSC-enriched tumorspheres from an Her2⁺ breast cancer cell line with that of the more differentiated parental cells. Among the molecules strongly upregulated in tumorspheres we selected the transmembrane amino-acid antiporter xCT. In this review, we summarize the results we obtained with different xCT-targeting vaccines. We show that, despite xCT being a self-antigen, vaccination was able to induce a humoral immune response that delayed primary tumor growth and strongly impaired pulmonary metastasis formation in mice challenged with tumorsphere-derived cells. Moreover, immunotargeting of xCT was able to increase CSC chemosensitivity to doxorubicin, suggesting that it may act as an adjuvant to chemotherapy. In conclusion, our approach based on the comparison of the transcriptome of tumorspheres and parental cells allowed us to identify a novel CSC-related target and to develop preclinical therapeutic approaches able to impact on CSC biology, and therefore, hampering tumor growth and dissemination.

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Table of Contents

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Editorial Board w/barcode

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The importance of appropriate control groups in perioperative analgesic studies: One size does not fit all

Postoperative pain remains poorly treated [1]. Specifically in the United States, opioids continue to be the main weapon used by clinicians to optimize postoperative analgesia [2]. Nonetheless, opioids can worsen patient reported quality of postoperative recovery [3,4]. In addition, the current national focus in the US to reduce the prescription of opioid analgesics and, subsequently, opioid diversion makes the use of multimodal analgesic strategies a very important topic in the perioperative care of surgical patients [5].

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We need more studies to guide the perioperative management of high risk seniors undergoing surgery

The number of surgical procedures in the ambulatory care setting in the United States has increased by over 300% during the past decade with over 30 million ambulatory surgeries (AS) being performed yearly [1]. Of these, 6 million are done in seniors (≥65years of age) and, with the aging of the US population, the number of seniors undergoing surgery will expand exponentially. In addition, more complex surgeries (e.g. hysterectomy, thyroidectomy, spine surgery) are also now conducted in the ambulatory setting [2–4].

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