Abstract：
PURPOSE:There is a need for biomarkers of drug efficacy for targeted therapies in triple-negative breast cancer (TNBC). As a step toward this, we identify multi-omic molecular determinants of anti-TNBC efficacy in cell lines for a panel of oncology drugs. METHODS:Using 23 TNBC cell lines, drug sensitivity scores (DSS3) were determined using a panel of investigational drugs and drugs approved for other indications. Molecular readouts were generated for each cell line using RNA sequencing, RNA targeted panels, DNA sequencing, and functional proteomics. DSS3 values were correlated with molecular readouts using a FDR-corrected significance cutoff of p* < 0.05 and yielded molecular determinant panels that predict anti-TNBC efficacy. RESULTS:Six molecular determinant panels were obtained from 12 drugs we prioritized based on their efficacy. Determinant panels were largely devoid of DNA mutations of the targeted pathway. Molecular determinants were obtained by correlating DSS3 with molecular readouts. We found that co-inhibiting molecular correlate pathways leads to robust synergy across many cell lines. CONCLUSIONS:These findings demonstrate an integrated method to identify biomarkers of drug efficacy in TNBC where DNA predictions correlate poorly with drug response. Our work outlines a framework for the identification of novel molecular determinants and optimal companion drugs for combination therapy based on these correlates.
journal_name
Breast Cancer Res Treatjournal_title
Breast cancer research and treatmentauthors
Merrill NM,Lachacz EJ,Vandecan NM,Ulintz PJ,Bao L,Lloyd JP,Yates JA,Morikawa A,Merajver SD,Soellner MBdoi
10.1007/s10549-019-05473-9subject
Has Abstractpub_date
2020-01-01 00:00:00pages
337-347issue
2eissn
0167-6806issn
1573-7217pii
10.1007/s10549-019-05473-9journal_volume
179pub_type
杂志文章abstract：:Cell migration is essential in many diverse processes ranging from embryonic development to wound healing and immune response. Cancer cells have recently been shown to utilize chemoattraction mechanisms mediated by chemokines and their respective receptors, e.g., the CXCL12/CXCR4 pathway normally found in leukocytes. ...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-007-9504-0
更新日期：2007-12-01 00:00:00
abstract：:Triple negative breast cancer (TNBC) is an aggressive clinical phenotype characterized by lack of expression (or minimal expression) of estrogen receptor (ER) and progesterone receptor (PR) as well as an absence of human epidermal growth factor receptor-2 (HER2) overexpression. It shows substantial overlap with basal-...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章,评审
doi：10.1007/s10549-010-1293-1
更新日期：2011-02-01 00:00:00
abstract：:Alcohol consumption is a risk factor for breast cancer in humans. Experimental studies indicate that alcohol exposure promotes malignant progression of mammary tumors. However, the underlying cellular and molecular mechanisms remain unclear. Alcohol induces a pro-inflammatory response by modulating the expression of c...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-011-1902-7
更新日期：2012-06-01 00:00:00
abstract：BACKGROUND:The outcome of breast cancer is usually determined by multiple factors. Serum tumor necrosis factor alpha concentration has been found to be increased in the circulation of patients with malignancy. This study was designed with the aim to investigate any correlation between the serum tumor necrosis factor al...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1023/a:1005736712307
更新日期：1997-05-01 00:00:00
abstract：BACKGROUND:The homeobox (HOX) family consists of 39 genes whose expressions are tightly controlled and coordinated within the family, during development. We performed a comprehensive analysis of this gene family in cancer settings. METHODS:Gene correlation analysis was performed using breast cancer data available in T...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-020-06087-2
更新日期：2021-01-18 00:00:00
abstract：PURPOSE:The malignant upgrade rate of flat epithelial atypia (FEA) diagnosed on core needle biopsy varies between 0 and 30%. Excision versus observation with radiological follow-up for these lesions remains controversial. We hypothesize that the local rate of FEA is low and that close radiological surveillance is a rea...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-019-05481-9
更新日期：2020-01-01 00:00:00
abstract：:Manganese superoxide dismutase (MnSOD) is known to play a role in cancer. MnSOD exerts a tumor suppressive effect in estrogen-dependent human breast cancer cells. In the present study we investigated the in vitro role of MnSOD in the growth of some aggressive and highly metastatic estrogen-independent breast cancer ce...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-007-9597-5
更新日期：2008-03-01 00:00:00
abstract：:The uptake and retention of a radiolabeled synthetic progestin ORG 2058 by the mammary glands were examined in the baboon. Four estrogen-primed baboons were injected intravenously with 2.5 micrograms/kg body weight of 3H-ORG 2058. One animal received an additional injection of 2.5 mg/kg body weight of unlabeled proges...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/BF01806397
更新日期：1984-01-01 00:00:00
abstract：BACKGROUND:To investigate the correlation among some of the commonly used clinical, pathological factors and newer biological indicators, and to identify the independent predictors of distant metastasis at presentation in patients with breast cancer. METHODS:The pathological specimens from 73 patients with breast canc...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1023/a:1012269804578
更新日期：2001-08-01 00:00:00
abstract：AIMS:Rapamycin and its analogues are currently being tested in clinical trials as novel-targeted anticancer agents. Pre-clinical studies that used breast cancer cell lines have suggested that p-Akt or p-S6K1 expressing tumors, as well as PTEN negative tumors, were sensitive to rapamycin. The aims of this study were to ...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-007-9746-x
更新日期：2008-08-01 00:00:00
abstract：:The possible role of personality patterns and psychosocial factors in breast cancer has been studied extensively, through both human and animal experiments. The data are conflicting, and the conclusions controversial. This review will serve two purposes. First, we present evidence that behavioral patterns most commonl...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章,评审
doi：10.1023/a:1005964511134
更新日期：1997-11-01 00:00:00
abstract：:Germline mutations in BRCA1/2 confer a high risk of breast cancer (BC), but the magnitude of this risk varies according to various factors. Although controversial, there are data to support the hypothesis of allelic-risk heterogeneity. We assessed variation in BC risk according to the location of mutations recorded in...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-011-1655-3
更新日期：2011-12-01 00:00:00
abstract：:Aurora kinases (AKs) regulate multiple components of mitotic cell division in eukaryotic cells. Aurora A is frequently amplified or overexpressed in breast cancer cells leading to aberrant chromosome segregation, genomic instability, and activation of oncogenic pathways. In the present studies, we determined the effec...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-012-2171-9
更新日期：2012-09-01 00:00:00
abstract：:Previous investigations into the relationship of CAG-repeat lengths in the androgen receptor (AR) gene to female breast cancer (BC) have yielded somewhat confusing results. Decreased AR transactivational activity lowers androgen:estrogen balance, and may thereby effect functional hyperestrogenicity. This may promote t...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1023/a:1012942910375
更新日期：2001-11-01 00:00:00
abstract：:The structure/activity relationships for inhibition of aromatase and cholesterol side-chain cleavage enzyme (CSCC) by aminoglutethimide and some of its analogues are reviewed. Although more effective against aromatase than CSCC, aminoglutethimide markedly inhibits both enzymes. Optimal competitive antagonism of aromat...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：
更新日期：1986-01-01 00:00:00
abstract：:The clinical benefit of eribulin versus capecitabine was evaluated using health-related quality of life (HRQoL) data from a phase 3 randomized trial in patients with pretreated advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT00337103). The study population has been described previously (Kaufman et...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章,多中心研究,随机对照试验
doi：10.1007/s10549-015-3633-7
更新日期：2015-12-01 00:00:00
abstract：:Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate with demonstrated anti-proliferative and anti-cancer activity in mammary cells. We hypothesized that IP6 modulates cell cycle proteins by action on cytoplasmic signaling molecules. The effects of both pharmacological (2 mM) and physi...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-004-6456-5
更新日期：2005-05-01 00:00:00
abstract：:GB3 and GB5 are mouse monoclonal antibodies raised against human amnion. GB3 detects the epidermal basement membrane, and GB5 reacts with the junctional substances between the epithelial cells. These two antibodies were studied on breast tissues by indirect immunofluorescence. All (n = 8) of the normal mammary glandul...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/BF01807700
更新日期：1986-01-01 00:00:00
abstract：:The Breast Imaging Reporting and Data System (BI-RADS) was introduced in 1993 to standardize the interpretation of mammograms. Though many studies have assessed the validity of the system, fewer have examined its reliability. Our objective is to identify predictors of reliability as measured by the kappa statistic. We...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章,评审
doi：10.1007/s10549-010-0770-x
更新日期：2010-04-01 00:00:00
abstract：:Ductal carcinoma in situ (intraductal carcinoma) of the breast is a commonly recognized and curable clinical entity. Patients with intraductal carcinoma are at risk to develop invasive breast cancer presumably due to a transition from the noninvasive to the invasive phase of growth. Primary breast malignancies commonl...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/BF00689717
更新日期：1995-06-01 00:00:00
abstract：:Xeroradiography of the axilla was performed in 132 patients with operable breast cancer to investigate the status of the axillary lymph nodes. Pathologic findings were correlated with the results of clinical examination and xeroradiographic findings. Xeroradiography does not appear to have improved our ability to iden...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/BF01807590
更新日期：1983-01-01 00:00:00
abstract：BACKGROUND:The aim was to prove the low identification rate of sentinel lymph node biopsy (SNB) and to determine the feasibility of replacing axillary lymph node dissection (AND) in axillary lymph node positive patients after chemotherapy. METHODS:From October 2001 to July 2005, 875 consecutive patients with primary o...
journal_title：Breast cancer research and treatment
pub_type： 临床试验,杂志文章
doi：10.1007/s10549-006-9330-9
更新日期：2007-05-01 00:00:00
abstract：:The aim of this study is to evaluate the impact of CYP2D6 genotyping in predicting disease-free survival and toxicity in breast cancer patients treated with adjuvant tamoxifen. DNA from 91 patients was genotyped using the AmpliChip CYP450 GeneChip, Roche that facilitates the classification of individuals by testing 27...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-009-0328-y
更新日期：2010-01-01 00:00:00
abstract：:MicroRNAs play a role in breast cancer development and progression by post-transcriptional repression of the expression of important genes, such as the tumor suppressor gene phosphatase and tensin homolog (PTEN). The focus of the current study was to examine the diagnostic potential of circulating cell-free microRNAs ...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-012-1988-6
更新日期：2012-08-01 00:00:00
abstract：BACKGROUND:We have developed a decision analysis model that uses the results of available randomized controlled trials to model the natural history of early breast cancer and assess the potential clinical and financial effects of using adjuvant therapies. PATIENTS AND METHODS:The original model was used to assess the ...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/BF00662134
更新日期：1993-01-01 00:00:00
abstract：:Elevated body weight is a risk factor for postmenopausal breast cancer and is associated with increased incidence of spontaneous and chemically induced mammary tumors (MTs) in rodents. In this study, genetically obese Lep(ob)Lep(ob) female mice that overexpress human TGF-alpha (transforming growth factor-alpha) were u...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1023/a:1021891825399
更新日期：2003-02-01 00:00:00
abstract：PURPOSE:Differences in tumor biology, genomic architecture, and health care delivery patterns contribute to the breast cancer mortality gap between White and Black patients in the US. Although this gap has been well documented in previous literature, it remains uncertain how large the actual effect size of race is for ...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-020-05984-w
更新日期：2020-10-27 00:00:00
abstract：:Few studies have assessed the agreement between subjects' self-report and medical records among patients with breast cancer (BC), and none has addressed this issue in low-income women with BC. We assessed the level of agreement between self-report and medical records data for key BC treatment and prognostic characteri...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-009-0447-5
更新日期：2010-02-01 00:00:00
abstract：:Axillary management in breast cancer is becoming increasingly conservative. This approach is based on the identification of low axillary burden on sentinel node biopsy (SNB). The modern practice of routine pre-operative axillary ultrasound has meant that patients are 'fast tracked' to axillary node clearance (ANC) in ...
journal_title：Breast cancer research and treatment
pub_type： 社论
doi：10.1007/s10549-017-4313-6
更新日期：2017-09-01 00:00:00
abstract：BACKGROUND:Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, lacking effective targeted therapies, and whose underlying mechanisms are still unclear. The gene coding for Gametogenetin-binding protein (GGNBP2), also known as Zinc Finger Protein 403 (ZNF403), is located on chromosome 1...
journal_title：Breast cancer research and treatment
pub_type： 杂志文章
doi：10.1007/s10549-018-5052-z
更新日期：2019-02-01 00:00:00
