Abstract:
INTRODUCTION:17-allyamino-17-demethoxygeldanamycin (17-AAG), a small molecule inhibitor of Hsp90, is currently in clinical trials in breast cancer. However, 17-AAG treatment often results in inhibition of tumor growth rather than shrinkage, making detection of response a challenge. Magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) are noninvasive imaging methods than can be used to monitor metabolic biomarkers of drug-target modulation. This study set out to examine the MRS-detectable metabolic consequences of Hsp90 inhibition in a breast cancer model. METHODS:MCF-7 breast cancer cells were investigated, and MRS studies were performed both on live cells and on cell extracts. (31)P and (1)H MRS were used to determine total cellular metabolite concentrations and (13)C MRS was used to probe the metabolism of [1,2-(13)C]-choline. To explain the MRS metabolic findings, microarray and RT-PCR were used to analyze gene expression, and in vitro activity assays were performed to determine changes in enzymatic activity following 17-AAG treatment. RESULTS:Treatment of MCF-7 cells with 17-AAG for 48 hours caused a significant increase in intracellular levels of choline (to 266 ± 18% of control, P = 0.05) and phosphocholine (PC; to 181 ± 10% of control, P = 0.001) associated with an increase in expression of choline transporter SLC44A1 and an elevation in the de novo synthesis of PC. We also detected an increase in intracellular levels of glycerophosphocholine (GPC; to 176 ± 38% of control, P = 0.03) associated with an increase in PLA2 expression and activity. CONCLUSIONS:This study determined that in the MCF-7 breast cancer model inhibition of Hsp90 by 17-AAG results in a significant MRS-detectable increase in choline, PC and GPC, which is likely due to an increase in choline transport into the cell and phospholipase activation. (1)H MRSI can be used in the clinical setting to detect levels of total choline-containing metabolite (t-Cho, composed of intracellular choline, PC and GPC). As Hsp90 inhibitors enter routine clinical use, t-Cho could thus provide an easily detectable, noninvasive metabolic biomarker of Hsp90 inhibition in breast cancer patients.
journal_name
Breast Cancer Resjournal_title
Breast cancer research : BCRauthors
Brandes AH,Ward CS,Ronen SMdoi
10.1186/bcr2729subject
Has Abstractpub_date
2010-01-01 00:00:00pages
R84issue
5eissn
1465-5411issn
1465-542Xpii
bcr2729journal_volume
12pub_type
杂志文章abstract:BACKGROUND:Breast cancer is a highly heterogeneous disease characterized by multiple histologic and molecular subtypes. While a myriad of breast cancer cell lines have been developed over the past 60 years, estrogen receptor alpha (ER)+ disease and some mutations associated with this subtype remain underrepresented. He...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-020-01300-y
更新日期:2020-06-23 00:00:00
abstract:INTRODUCTION:The status of tumor-infiltrating lymphocytes (TILs) has been recently proposed to predict clinical outcome of patients with breast cancer. We therefore studied the prognostic significance of CD8(+) TILs and FOXP3(+) TILs in residual tumors after neoadjuvant chemotherapy (NAC) and the alterations in these p...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,多中心研究
doi:10.1186/s13058-015-0632-x
更新日期:2015-09-04 00:00:00
abstract:INTRODUCTION:Tamoxifen, a selective estrogen receptor (ER) modulator, may affect cancer cell survival through mechanisms other than ER antagonism. In the present study, we tested the efficacy of tamoxifen in a panel of ER-negative breast cancer cell lines and examined the drug mechanism. METHODS:In total, five ER-nega...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-014-0431-9
更新日期:2014-09-17 00:00:00
abstract:BACKGROUND:Tumor hypoxia is an independent prognostic factor associated with poor patient survival. Emerging evidence suggests that hypoxia can potentially maintain or enhance the stem cell phenotype of both normal stem cells and cancer cells. However, it remains to be determined whether cell fate is regulated in vivo ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-018-0944-8
更新日期:2018-03-06 00:00:00
abstract:BACKGROUND:Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry. METHODS:We evaluated 88 breast cancer risk variant...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-016-0786-1
更新日期:2016-12-08 00:00:00
abstract:INTRODUCTION:Increased mammographic breast density is one of the strongest risk factors for breast cancer. While two-thirds of the variation in mammographic density appears to be genetically influenced, few variants have been identified. We examined the association of inherited variation in genes from pathways that med...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3088
更新日期:2012-01-07 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:AIB1, located at 20q12, is a member of the steroid hormone coactivator family. It contains a glutamine repeat (CAG/CAA) polymorphism at its carboxyl-terminal region that may alter the transcriptional activation of the receptor and affect susceptibility to breast cancer through altered sensitivity to hormon...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr1009
更新日期:2005-01-01 00:00:00
abstract:INTRODUCTION:Experimental evidence suggests a protective role for circulating 25-hydroxyvitamin D (25(OH)D) in breast cancer development, but the results of epidemiological studies have been inconsistent. METHODS:We conducted a case-control study nested within two prospective cohorts, the New York University Women's H...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3390
更新日期:2013-02-26 00:00:00
abstract:INTRODUCTION:Inhibition of phosphatidylinositol-3-kinase (PI3K) induces apoptosis when combined with estrogen deprivation in estrogen receptor (ER)-positive breast cancer. The aims of the present study were to identify effective PI3K pathway inhibitor and endocrine therapy combinations, to evaluate the effect of PI3K p...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2833
更新日期:2011-03-01 00:00:00
abstract:INTRODUCTION:Current approaches to inhibit oestrogen receptor-alpha (ERα) are focused on targeting its hormone-binding pocket and have limitations. Thus, we propose that inhibitors that bind to a coactivator-binding pocket on ERα, called activation function 2 (AF2), might overcome some of these limitations. METHODS:In...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-015-0529-8
更新日期:2015-02-25 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:INTRODUCTION:With the improvement of therapeutic options for the treatment of breast cancer, the development of brain metastases has become a major limitation to life expectancy in many patients. Therefore, our aim was to identify molecular markers associated with the development of brain metastases in breast cancer. ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3150
更新日期:2012-03-19 00:00:00
abstract:INTRODUCTION:Bisphosphonates have become standard therapy for the treatment of skeletal complications related to breast cancer. Although their therapeutic effects mainly result from an inhibition of osteoclastic bone resorption, in vitro data indicate that they also act directly on breast cancer cells, inhibiting proli...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr1845
更新日期:2008-01-01 00:00:00
abstract::Aromatase inhibitors are currently included in the 'optimal' management of early-stage breast cancer. Uncertainty remains, however, as to the most appropriate treatment strategy, particularly for newly diagnosed women as they seek to trade off the cost, toxicities and efficacy of the treatment options. Recent publicat...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr2410
更新日期:2009-01-01 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:INTRODUCTION:Primary breast cancer involving four or more axillary lymph nodes carries a poor prognosis. We hypothesized that use of an immunohistochemical biomarker scoring system could allow for identification of variable risk subgroups. METHODS:Patients with four or more positive axillary nodes were identified from...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,随机对照试验
doi:10.1186/bcr1847
更新日期:2008-01-01 00:00:00
abstract:INTRODUCTION:Earlier menarche is related to subsequent breast cancer risk, yet international differences in the age and tempo of other pubertal milestones and their relationships with body mass index (BMI) are not firmly established in populations at differing risk for breast cancer. We compared age and tempo of adrena...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-014-0469-8
更新日期:2014-11-15 00:00:00
abstract::Hypoxia-inducible factor-1 (HIF), which is centrally involved in physiological oxygen homeostasis, is also activated in the majority of tumours. Activation of HIF can occur through genetic mechanisms or as a result of hypoxia within the tumour microenvironment. In some cases HIF activation appears to be intimately lin...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr313
更新日期:2001-01-01 00:00:00
abstract:BACKGROUND:Dysregulated DNA repair and cell proliferation controls are essential driving forces in mammary tumorigenesis. BCCIP was originally identified as a BRCA2 and CDKN1A interacting protein that has been implicated in maintenance of genomic stability, cell cycle regulation, and microtubule dynamics. The aims of t...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-017-0907-5
更新日期:2017-10-18 00:00:00
abstract:INTRODUCTION:Aromatase inhibitor-associated arthralgia (AIAA) is a common and often debilitating symptom in breast cancer survivors. Since joint symptoms have been related to estrogen deprivation through the menopausal transition, we hypothesized that genetic polymorphisms in CYP19A1, the final enzyme in estrogen synth...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2813
更新日期:2011-01-20 00:00:00
abstract::Recent studies indicate that constitutive signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway is a cause of treatment resistance in breast cancer patients. This implies that patients with tumors that exhibit aberrant PI3K signaling may benefit from targeted pathway inhibitors. The first agents to make ...
journal_title:Breast cancer research : BCR
pub_type: 评论,杂志文章
doi:10.1186/bcr1307
更新日期:2005-01-01 00:00:00
abstract:BACKGROUND:Chromogenic in situ hybridization (CISH) is emerging as a practical, cost-effective, and valid alternative to fluorescent in situ hybridization in testing for gene alteration, especially in centers primarily working with immunohistochemistry (IHC). METHODS:We assessed Her-2/neu alteration using CISH on form...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr915
更新日期:2004-01-01 00:00:00
abstract:BACKGROUND:CRIPTO is a multi-functional signaling protein that promotes stemness and oncogenesis. We previously developed a CRIPTO antagonist, ALK4L75A-Fc, and showed that it causes loss of the stem cell phenotype in normal mammary epithelia suggesting it may similarly inhibit CRIPTO-dependent plasticity in breast canc...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-020-01361-z
更新日期:2020-11-13 00:00:00
abstract:INTRODUCTION:Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase that is highly expressed in Human Epidermal Growth Factor 2(+) (Her2(+)) breast cancers. Overexpression of PTK6 enhances anchorage-independent survival, proliferation, and migration of breast cancer cells. We hypothesized that PTK6 inhibiti...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-015-0594-z
更新日期:2015-06-19 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::Various methods are available for the measurement of proliferation rates in tumours, including mitotic counts, estimation of the fraction of cells in S-phase of the cell cycle and immunohistochemistry of proliferation-associated antigens. The evidence, advantages and disadvantages for each of these methods along with ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr1618
更新日期:2006-01-01 00:00:00
abstract::Breast cancer risk is continuing to increase across all societies with rates in countries with traditionally lower risks catching up with the higher rates in the Western world. Although cure rates from breast cancer have continued to improve such that absolute numbers of breast cancer deaths have dropped in many count...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-015-0595-y
更新日期:2015-07-09 00:00:00
abstract:BACKGROUND:Women with breast cancer who have multiple affected relatives are more likely to have inherited genetic risk factors for the disease. All the currently known genetic risk factors for breast cancer account for less than half of the average familial risk. Furthermore, the genetic factor(s) underlying an increa...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-017-0825-6
更新日期:2017-03-16 00:00:00
abstract:INTRODUCTION:Mammary-specific overexpression of Six1 in mice induces tumors that resemble human breast cancer, some having undergone epithelial to mesenchymal transition (EMT) and exhibiting stem/progenitor cell features. Six1 overexpression in human breast cancer cells promotes EMT and metastatic dissemination. We hyp...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3219
更新日期:2012-07-05 00:00:00