Abstract:
INTRODUCTION:Human epidermal growth factor receptor-2 (HER2) gene amplification (HER2+) drives tumor cell growth and survival in ~25% of breast cancers. HER2 signaling activates the type I phosphoinositide 3-kinase (PI3K), upon which these tumors rely. Consequently, inhibitors of HER2 and type I PI3K block growth and increase apoptosis in HER2+ breast cancers, especially when used in combination. However, the impact of type III PI3K inhibition, particularly in combination with HER2 blockade or type I PI3K inhibition, remains less clear. METHODS:We utilized small molecule kinase inhibitors, locked nucleic acid antisense oligonucleotides (LNA-ASOs), and siRNA to assess proliferation, autophagy, apoptosis, and protein expression in cell culture models of HER2+ breast cancers. RESULTS:Treatment of HER2+ breast cancer cells with HER2 inhibitors or type I PI3K kinase inhibitors, alone or in combination, blocked type I PI3K signaling, reduced tumor cell growth, and induced autophagy. Knockdown of the type I PI3K, p110α, using an LNA-ASO termed EZN4150 inhibited PI3K-mediated Akt phosphorylation. However, in contrast to catalytic inhibitors of type I PI3Ks, EZN4150 did not induce autophagy, and blocked autophagy in response to inhibitors of HER2 or type I PI3Ks in a dominant fashion. Sequence analysis of EZN4150 revealed significant homology to the gene encoding the type III PI3K, Vps34, a key component for autophagy induction. EZN4150 simultaneously reduced expression of both p110α and Vps34. Combined inhibition of PI3K signaling and autophagy using individual siRNAs against p110α and Vps34 or using pharmacological type I and type III PI3K inhibitors recapitulated what was seen with EZN4150, and robustly enhanced tumor cell killing. CONCLUSIONS:These studies highlight the important role of Vps34-mediated autophagy in limiting the anti-tumor response to inhibitors of HER2 or type I PI3K in HER2+ breast cancers. The type III PI3K Vps34 represents a potential therapeutic target to block treatment-induced autophagy and enhance tumor cell killing.
journal_name
Breast Cancer Resjournal_title
Breast cancer research : BCRauthors
Young CD,Arteaga CL,Cook RSdoi
10.1186/s13058-015-0656-2subject
Has Abstractpub_date
2015-12-04 00:00:00pages
148eissn
1465-5411issn
1465-542Xpii
10.1186/s13058-015-0656-2journal_volume
17pub_type
杂志文章abstract:BACKGROUND:The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry. METHODS:BC mutation carrier cases from...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-020-01341-3
更新日期:2020-10-21 00:00:00
abstract::Over the past 8 years there has been a wealth of breast cancer gene expression studies. The majority of these studies have focused upon characterising a tumour at presentation, before treatment, rather than looking at the effects of treatment on the tumour. More recently, a number of groups have moved from predicting ...
journal_title:Breast cancer research : BCR
pub_type: 评论,社论
doi:10.1186/bcr2196
更新日期:2008-01-01 00:00:00
abstract:BACKGROUND:E74-like factor 5 (ELF5) is an epithelial-specific member of the E26 transforming sequence (ETS) transcription factor family and a critical regulator of cell fate in the placenta, pulmonary bronchi, and milk-producing alveoli of the mammary gland. ELF5 also plays key roles in malignancy, particularly in basa...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-015-0666-0
更新日期:2016-01-07 00:00:00
abstract:INTRODUCTION:Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) has been shown to enhance breast cancer cell survival and confer resistance to chemotherapeutic agents. We studied the prognostic and predictive value of PIK3CA mutations a...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-014-0405-y
更新日期:2014-07-24 00:00:00
abstract:INTRODUCTION:Surgery is currently the definitive treatment for early-stage breast cancer. However, the rate of positive surgical margins remains unacceptably high. The human sodium iodide symporter (hNIS) is a naturally occurring protein in human thyroid tissue, which enables cells to concentrate radionuclides. The hNI...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3404
更新日期:2013-03-18 00:00:00
abstract:INTRODUCTION:Breast carcinoma is the most common cancer in women, but its incidence is not increased in Lynch syndrome (LS) and studies on DNA mismatch repair deficiency (MMR) in LS-associated breast cancers have arrived at conflicting results. This study aimed to settle the question as to whether breast carcinoma belo...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3205
更新日期:2012-06-12 00:00:00
abstract:INTRODUCTION:The potential of applying data analysis tools to microarray data for diagnosis and prognosis is illustrated on the recent breast cancer dataset of van 't Veer and coworkers. We re-examine that dataset using the novel technique of logical analysis of data (LAD), with the double objective of discovering patt...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr1512
更新日期:2006-01-01 00:00:00
abstract:INTRODUCTION:Triple-negative breast cancer does not express estrogen and progesterone receptors, and no overexpression/amplification of the HER2-neu gene occurs. Therefore, this subtype of breast cancer lacks the benefits of specific therapies that target these receptors. Today chemotherapy is the only systematic thera...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2606
更新日期:2010-01-01 00:00:00
abstract:BACKGROUND:Breast cancer is a heterogeneous disease. Hence, stratification of patients based on the subtype of breast cancer is key to its successful treatment. Among all the breast cancer subtypes, basal-like breast cancer is the most aggressive subtype with limited treatment options. Interestingly, we found focal adh...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-020-01298-3
更新日期:2020-06-03 00:00:00
abstract:INTRODUCTION:Breast cancer subtyping and prognosis have been studied extensively by gene expression profiling, resulting in disparate signatures with little overlap in their constituent genes. Although a previous study demonstrated a prognostic concordance among gene expression signatures, it was limited to only one da...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,meta分析
doi:10.1186/bcr2124
更新日期:2008-01-01 00:00:00
abstract::High-throughput screening is an essential component of the toolbox of modern technologies that improve speed and efficiency in contemporary cancer drug development. This is particularly important as we seek to exploit, for maximum therapeutic benefit, the large number of new molecular targets emerging from the Human G...
journal_title:Breast cancer research : BCR
pub_type: 社论
doi:10.1186/bcr440
更新日期:2002-01-01 00:00:00
abstract::A recent analysis by the Collaborative Group on Hormonal Factors in Breast Cancer has provided the most precise quantification to date of the familial risks of breast cancer. The familial relative risks are shown to decrease from more than fivefold in women younger than age 40 years with a first-degree relative aged y...
journal_title:Breast cancer research : BCR
pub_type: 社论
doi:10.1186/bcr448
更新日期:2002-01-01 00:00:00
abstract::Preclinical investigations and selected clinical observational studies support an association between higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk. However, the recently updated report from the Institute of Medicine concluded that, for cancer and vitamin D, the evidence was 'inc...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr2846
更新日期:2011-08-16 00:00:00
abstract:BACKGROUND:Breast cancer patients with early-stage disease are increasingly administered neoadjuvant chemotherapy (NAC) to downstage their tumors prior to surgery. In this setting, approximately 31% of patients fail to respond to therapy. This demonstrates the need for techniques capable of providing personalized feedb...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-020-01262-1
更新日期:2020-03-13 00:00:00
abstract::Improvements in the detection and treatment of breast cancer have dramatically altered its clinical course and outcome. However, prevention of breast cancer remains an elusive goal. Parity, age of menarche, and age at menopause are major risk factors drawing attention to the important role of the endocrine system in d...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr431
更新日期:2002-01-01 00:00:00
abstract::Gene therapy is a therapeutic approach that is designed to correct specific molecular defects that contribute to the cause or progression of cancer. Genes that are mutated or deleted in cancers include the cancer susceptibility genes p53 and BRCA1. Because mutational inactivation of gene function is specific to tumor ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr26
更新日期:2000-01-01 00:00:00
abstract:INTRODUCTION:Estrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the regulatory region of estrogen-responsive genes and regulates their transcription. Sequence variants in the regulatory regions have the potential to affect the transcription factor-regulatory sequ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-014-0455-1
更新日期:2014-10-09 00:00:00
abstract:BACKGROUND:MicroRNAs (miRNAs) regulate gene expression and influence cancer. Primary transcripts of miRNAs (pri-miRNAs) are poorly annotated and little is known about the role of germline variation in miRNA genes and breast cancer (BC). We sought to identify germline miRNA variants associated with BC risk and tumor sub...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-018-0964-4
更新日期:2018-06-05 00:00:00
abstract:BACKGROUND:The isocitrate dehydrogenase (IDH) gene family expresses key functional metabolic enzymes in the Krebs cycle and mediates the epigenetic reprogramming, which serves as an important biomarker of breast cancer. However, the expression levels of the IDH protein and their biological function in human breast canc...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-018-0953-7
更新日期:2018-04-16 00:00:00
abstract::Targeting the function of epidermal growth factor receptor (EGFR) has failed as an effective clinical option for breast cancer. Understanding the drivers of inherent resistance has been a challenge. One possible mechanism is the acquisition of stem-like properties through the process of epithelial-mesenchymal transiti...
journal_title:Breast cancer research : BCR
pub_type: 评论,杂志文章
doi:10.1186/s13058-014-0448-0
更新日期:2014-09-23 00:00:00
abstract:BACKGROUND:The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear. METHODS:We have c...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr419
更新日期:2002-01-01 00:00:00
abstract:INTRODUCTION:Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Our aims in this study were (1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgic...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-014-0447-1
更新日期:2014-10-31 00:00:00
abstract:INTRODUCTION:Insulin-like growth factor binding protein-3 (IGFBP-3) differentially modulates breast epithelial cell growth through insulin-like growth factor (IGF)-dependent and IGF-independent pathways and is a direct (IGF-independent) growth inhibitor as well as a mitogen that potentiates EGF (epidermal growth factor...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr963
更新日期:2005-01-01 00:00:00
abstract::The potential for a reduction in dietary fat or for an increase in dietary fiber to reduce breast cancer risk has been debated for some years. It is argued here that available research data, even though extensive, leave open hypotheses ranging from little or no potential to major public health potential for breast can...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr68
更新日期:2000-01-01 00:00:00
abstract:BACKGROUND:Metastasis is the major cause of death from breast cancer. Colonization and adaption of metastatic cells in distant organs is a rate-limiting step of the cancer spreading. The underlying mechanisms responsible for the colonization of breast cancer to lung metastatic niches are not fully understood. METHODS:...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-019-1114-3
更新日期:2019-02-12 00:00:00
abstract:INTRODUCTION:Mutations in BRCA1 and BRCA2 confer a high risk of breast cancer (BC), but the magnitude of this risk seems to vary according to the study and various factors. Although controversial, there are data to support the hypothesis of allelic risk heterogeneity. METHODS:We assessed variation in BC risk according...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3218
更新日期:2012-07-03 00:00:00
abstract::Progesterone and estradiol, and their nuclear receptors, play essential roles in the physiology of the reproductive tract, the mammary gland and the nervous system. Estrogens have traditionally been considered associated with an increased risk of breast cancer. There is, however, compelling evidence that progesterone ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr539
更新日期:2002-01-01 00:00:00
abstract:INTRODUCTION:Pre-clinical data suggest p53-dependent anthracycline-induced apoptosis and p53-independent taxane activity. However, dedicated clinical research has not defined a predictive role for TP53 gene mutations. The aim of the current study was to retrospectively explore the prognosis and predictive values of TP5...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,随机对照试验
doi:10.1186/bcr3179
更新日期:2012-05-02 00:00:00
abstract:INTRODUCTION:Gene expression analysis is used to subtype breast cancers such that the most aggressive tumors are identified, but translating this into clinical practice can be cumbersome. Our goal is to develop a universal biomarker that distinguishes patients at high risk across all breast cancer subtypes. We previous...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2156
更新日期:2008-01-01 00:00:00
abstract:INTRODUCTION:Menopausal hormone therapy (HT) is typically withheld from breast cancer survivors because of concerns about risk for recurrence. Our objectives were to estimate the effects of HT on recurrence in breast cancer survivors and to examine the reliability of these estimates. METHODS:In a systematic review of ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,meta分析
doi:10.1186/bcr1035
更新日期:2005-01-01 00:00:00