Abstract:
BACKGROUND:The oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which it potently activates PI3K signalling. Antibody-mediated inhibition of this ERBB2/ERBB3/PI3K axis has been a cornerstone of treatment for ERBB2-amplified breast cancer patients for two decades. However, the lack of response and the rapid onset of relapse in many patients now question the assumption that the ERBB2/ERBB3 heterodimer is the sole relevant effector target of these therapies. METHODS:Through a systematic protein-protein interaction screen, we have identified and validated alternative RTKs that interact with ERBB2. Using quantitative readouts of signalling pathway activation and cell proliferation, we have examined their influence upon the mechanism of trastuzumab- and pertuzumab-mediated inhibition of cell growth in ERBB2-amplified breast cancer cell lines and a patient-derived xenograft model. RESULTS:We now demonstrate that inactivation of ERBB3/PI3K by these therapeutic antibodies is insufficient to inhibit the growth of ERBB2-amplified breast cancer cells. Instead, we show extensive promiscuity between ERBB2 and an array of RTKs from outside of the EGFR family. Paradoxically, pertuzumab also acts as an artificial ligand to promote ERBB2 activation and ERK signalling, through allosteric activation by a subset of these non-canonical RTKs. However, this unexpected activation mechanism also increases the sensitivity of the receptor network to the ERBB2 kinase inhibitor lapatinib, which in combination with pertuzumab, displays a synergistic effect in single-agent resistant cell lines and PDX models. CONCLUSIONS:The interaction of ERBB2 with a number of non-canonical RTKs activates a compensatory signalling response following treatment with pertuzumab, although a counter-intuitive combination of ERBB2 antibody therapy and a kinase inhibitor can overcome this innate therapeutic resistance.
journal_name
Breast Cancer Resjournal_title
Breast cancer research : BCRauthors
Kennedy SP,Han JZR,Portman N,Nobis M,Hastings JF,Murphy KJ,Latham SL,Cadell AL,Miladinovic D,Marriott GR,O'Donnell YEI,Shearer RF,Williams JT,Munoz AG,Cox TR,Watkins DN,Saunders DN,Timpson P,Lim E,Kolch W,Croucherdoi
10.1186/s13058-019-1127-ysubject
Has Abstractpub_date
2019-03-21 00:00:00pages
43issue
1eissn
1465-5411issn
1465-542Xpii
10.1186/s13058-019-1127-yjournal_volume
21pub_type
杂志文章abstract:BACKGROUND:Tumor-derived extracellular vesicles (tdEVs) and circulating tumor cells (CTCs) in the blood of metastatic cancer patients associate with poor outcomes. In this study, we explored the human epidermal growth factor receptor 2 (HER2) expression on CTCs and tdEVs of metastatic breast cancer patients. METHODS:B...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-020-01323-5
更新日期:2020-08-12 00:00:00
abstract:INTRODUCTION:Isoflavones are hypothesized to protect against breast cancer, but it is not clear whether they act as oestrogens or anti-oestrogens in breast tissue. Our aim was to determine the effects of taking a red clover-derived isoflavone supplement daily for 1 year on mammographic breast density. Effects on oestra...
journal_title:Breast cancer research : BCR
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1186/bcr773
更新日期:2004-01-01 00:00:00
abstract:INTRODUCTION:We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined. METHODS:HMG-CoAR protein and RNA expr...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2820
更新日期:2011-01-31 00:00:00
abstract::Testosterone binds to the androgen receptor in target tissue to mediate its effects. Variations in testosterone levels and androgen receptor activity may play a role in the etiology of breast cancer. Here, we review the epidemiologic evidence linking endogenous testosterone to breast cancer risk. Paradoxically, result...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr593
更新日期:2003-01-01 00:00:00
abstract::The Developmental Origins of Health and Disease (DOHaD) theory focuses on the consequences of periconceptional and in utero exposures. A wide range of environmental conditions during early development are now being investigated as a driving force for epigenetic disruptions that enhance disease risk in later life, incl...
journal_title:Breast cancer research : BCR
pub_type: 评论,社论
doi:10.1186/s13058-016-0760-y
更新日期:2016-10-12 00:00:00
abstract:INTRODUCTION:Radiation exposure at a young age is one of the strongest risk factors for breast cancer. Germline mutations in genes involved in the DNA-damage repair pathway (DDRP) may render women more susceptible to radiation-induced breast cancer. METHODS:We evaluated the contribution of germline mutations in the DD...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr1668
更新日期:2007-01-01 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 is a worldwide health problem and the leading cause of cancer death among females. We previously identified Jumonji domain containing 2A (JMJD2A) as a critical mediator of breast cancer proliferation, migration and invasion. We now report that JMJD2A could promote breast cancer progression th...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3667
更新日期:2014-05-30 00:00:00
abstract:INTRODUCTION:Although aberrant tyrosine kinase signalling characterises particular breast cancer subtypes, a global analysis of tyrosine phosphorylation in mouse models of breast cancer has not been undertaken to date. This may identify conserved oncogenic pathways and potential therapeutic targets. METHODS:We applied...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-014-0437-3
更新日期:2014-09-09 00:00:00
abstract:BACKGROUND:HER-2 (c-erbB2/Neu) predicts the prognosis of and may influence treatment responses in breast cancer. HER-2 activity induces the cytoplasmic location of p21WAFI/CIPI in cell culture, accompanied by resistance to apoptosis. p21WAFI/CIPI is a cyclin-dependent kinase inhibitor activated by p53 to produce cell c...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr654
更新日期:2003-01-01 00:00:00
abstract:INTRODUCTION:Human epidermal growth factor receptor HER3 has been implicated in promoting the aggressiveness and metastatic potential of breast cancer. Upregulation of HER3 has been found to be a major mechanism underlying drug resistance to EGFR and HER2 tyrosine kinase inhibitors and to endocrine therapy in the treat...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-015-0528-9
更新日期:2015-02-15 00:00:00
abstract:INTRODUCTION:Our efforts to prevent and treat breast cancer are significantly impeded by a lack of knowledge of the biology and developmental genetics of the normal mammary gland. In order to provide the specimens that will facilitate such an understanding, The Susan G. Komen for the Cure Tissue Bank at the IU Simon Ca...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3627
更新日期:2014-03-17 00:00:00
abstract:INTRODUCTION:During selective segregation of DNA, a cell asymmetrically divides and retains its template DNA. Asymmetric division yields daughter cells whose genome reflects that of the parents', simultaneously protecting the parental cell from genetic errors that may occur during DNA replication. We hypothesized that ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2754
更新日期:2010-01-01 00:00:00
abstract:INTRODUCTION:Matrix metalloproteinase (MMP)-2 is very active at degrading extracellular matrix. It is under the influence of an activator, membrane type 1 MMP (MMP-14), and the tissue inhibitor of metalloproteases (TIMP)-2. We hypothesized that the individual expression of these three markers or their balance may help ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr1503
更新日期:2006-01-01 00:00:00
abstract:INTRODUCTION:The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene with functions in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks. Based on family studies, women heterozygous for mutations in the ATM gene are reported to have a fourfold to fivefold increased risk of breast canc...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr809
更新日期:2004-01-01 00:00:00
abstract::Two articles previously published in Breast Cancer Research illustrate the high rates of breast cancer in Marin County, a wealthy, urban county immediately northwest of the city of San Francisco. I herein comment on these articles, and on the political/psychological/scientific dilemma presented by regions with high ca...
journal_title:Breast cancer research : BCR
pub_type: 评论,杂志文章,评审
doi:10.1186/bcr633
更新日期:2003-01-01 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::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: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::The increasing importance of signal transducer and activator of transcription 3 (STAT3) expression in human cancers has led several laboratories to examine in detail the expression of one of its major negative regulators in oncogenesis--the T-cell protein tyrosine phosphatase, nonreceptor type 2 (PTPN2). A recent pape...
journal_title:Breast cancer research : BCR
pub_type: 评论,杂志文章,评审
doi:10.1186/bcr3437
更新日期:2013-07-31 00:00:00
abstract:INTRODUCTION:The purpose of this work was to study the prognostic influence in breast cancer of thioredoxin reductase 1 (TXNRD1) and thioredoxin interacting protein (TXNIP), key players in oxidative stress control that are currently evaluated as possible therapeutic targets. METHODS:Analysis of the association of TXNR...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,多中心研究
doi:10.1186/bcr2599
更新日期:2010-01-01 00:00:00
abstract::A small proportion of breast cancers are due to a heritable predisposition. Recently, two predisposition genes, BRCA1 and BRCA2, have been identified and cloned. The morphological features of tumours from patients harbouring mutations in the BRCA1 and BRCA2 genes differ from each other and from sporadic breast cancers...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr10
更新日期:1999-01-01 00:00:00
abstract:INTRODUCTION:The chromodomain helicase DNA binding protein 5 (CHD5) has recently been identified as a tumor suppressor in a mouse model. The CHD5 locus at 1p36 is deleted, and its mutation has been detected in breast cancer. We, therefore, evaluated whether CHD5 plays a role in human breast cancer. METHODS:We screened...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3182
更新日期:2012-05-08 00:00:00
abstract::Women's perceptions of breast cancer risk are largely inaccurate and are often associated with high levels of anxiety about cancer. There are interesting cultural differences that are not well researched. Genetic risk counselling significantly improves accuracy of women's perceptions of risk, but not necessarily to th...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr83
更新日期:2000-01-01 00:00:00
abstract:BACKGROUND:Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and r...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-017-0916-4
更新日期:2017-11-28 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::The protective effect of an early full-term pregnancy is a well established phenomenon; in contrast, the molecular and cell-specific mechanisms that govern parity-specific changes in the mammary gland have not been well described. Recent studies signify a dramatic advance in our understanding of this phenomenon, and i...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr603
更新日期:2003-01-01 00:00:00
abstract:BACKGROUND:Breast adipocytes play important roles in both the development and function of mammary epithelial cells. Therefore, carcinoma-adipose stromal cell (ASC) interactions have been considered pivotal in supporting tumor growth in breast cancer. In addition, it has been demonstrated that the biological features of...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-017-0863-0
更新日期:2017-06-19 00:00:00
abstract:INTRODUCTION:Oestrogens can mediate some of their cell survival properties through a nongenomic mechanism that involves the mitogen-activated protein kinase (MAPK) pathway. The mechanism of this rapid signalling and its dependence on a membrane bound oestrogen receptor (ER), however, remains controversial. The role of ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr1509
更新日期:2006-01-01 00:00:00
abstract::Recent insights into the molecular and cellular mechanisms underlying cancer development have revealed that immune cells functionally regulate epithelial cancer development and progression. Moreover, accumulated clinical and experimental data indicate that the outcome of an immune response toward an evolving breast ne...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr1746
更新日期:2007-01-01 00:00:00