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 pathway mutations and estrogen dependency on tumor response, and to determine the relevance of PIK3CA mutation in recurrent disease. METHODS:The PI3K catalytic subunit inhibitor BKM120, the mammalian target of rapamycin (mTOR) inhibitor RAD001 and the dual PI3K/mTOR inhibitor BGT226 were tested against ER-positive breast cancer cell lines before and after long-term estrogen deprivation (LTED). The impact of estradiol deprivation and the ER downregulator fulvestrant on PI3K pathway inhibitor-induced apoptosis was assessed. PIK3CA hotspot mutation analysis was performed in 51 recurrent or metastatic breast cancers and correlated with ER status and survival. RESULTS:Drug-induced apoptosis was most marked in short-term estrogen-deprived cells with PIK3CA mutation and phosphatase and tensin homolog loss. Apoptosis was most highly induced by BGT226, followed by BKM120, and then RAD001. Estradiol antagonized PI3K inhibitor-induced apoptosis following short-term estrogen deprivation, emphasizing a role for estrogen-deprivation therapy in promoting PI3K inhibitor activity in the first-line setting. ER-positive MCF7 LTED cells exhibited relative resistance to PI3K pathway inhibition that was reversed by fulvestrant. In contrast, T47D LTED cells exhibited ER loss and ER-independent PI3K agent sensitivity. PIK3CA mutation was prevalent in relapsed ER-positive disease (48%) and was associated with persistent ER positivity and a late relapse pattern. CONCLUSIONS:Estrogen deprivation increased the apoptotic effects of PI3K and dual PI3K/mTOR inhibitors in ER-positive disease, providing a rationale for PI3K/aromatase inhibitor combinations as first-line therapy. In LTED cells, differential effects on ER expression may be a relevant consideration. When ER was persistently expressed, fulvestrant strongly promoted PI3K drug activity. When ER was lost, PI3K inhibitor monotherapy was sufficient to induce high-level apoptosis. Although tumors with PIK3CA mutation had a late recurrence pattern, these mutations were common in metastatic disease and were most often associated with persistent ER expression. Targeting PIK3CA mutant tumors with a PI3K pathway inhibitor and fulvestrant is therefore a feasible strategy for aromatase-inhibitor-resistant ER-positive relapsed breast cancer.
journal_name
Breast Cancer Resjournal_title
Breast cancer research : BCRauthors
Sanchez CG,Ma CX,Crowder RJ,Guintoli T,Phommaly C,Gao F,Lin L,Ellis MJdoi
10.1186/bcr2833subject
Has Abstractpub_date
2011-03-01 00:00:00pages
R21issue
2eissn
1465-5411issn
1465-542Xpii
bcr2833journal_volume
13pub_type
杂志文章abstract:INTRODUCTION:Menopausal hormone therapy has been reported to increase the risk of certain subtypes of breast cancer and to be associated with a favorable survival. These associations could either be due to an increased mammographic surveillance or to a biological effect. We assessed these associations in a Swedish coho...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,多中心研究
doi:10.1186/bcr2145
更新日期:2008-01-01 00:00:00
abstract:INTRODUCTION:Aberrant activation of Wnt/β-catenin signaling plays an important role in the pathogenesis of breast cancer. DACT1 (Dapper/Frodo) has been identified as involved in antagonizing Wnt/β-catenin signaling through interacting with Dishevelled (Dvl), a central mediator of Wnt signaling, whereas its role in brea...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3399
更新日期:2013-03-12 00:00:00
abstract::The Breast Cancer Site Group (BCSG) of the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) has conducted a wide variety of clinical trials focussing on large phase III trials of adjuvant chemotherapy, adjuvant hormonal therapy, and optimal delivery of adjuvant radiation therapy. The Group has al...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr979
更新日期:2005-01-01 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: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: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::Anti-angiogenic therapies have demonstrated their value in the setting of advanced cancer, and are being explored for use in micrometastatic disease. Recent preclinical studies suggest that adjuvant anti-vascular endothelial growth factor (VEGF) therapies may increase the risk of metastasis. How concerning are these p...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2250
更新日期:2009-01-01 00:00:00
abstract:INTRODUCTION:The majority of breast cancers that occur in BRCA1 mutation carriers (BRCA1 carriers) are estrogen receptor-negative (ER-). Therefore, it has been suggested that ER negativity is intrinsic to BRCA1 cancers and reflects the cell of origin of these tumors. However, approximately 20% of breast cancers that de...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2776
更新日期:2010-01-01 00:00:00
abstract:INTRODUCTION:Involution of the mammary gland is a complex process of controlled apoptosis and tissue remodelling. The aim of the project was to identify genes that are specifically involved in this process. METHODS:We used Affymetrix oligonucleotide microarrays to perform a detailed transcript analysis on the mechanis...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr753
更新日期:2004-01-01 00:00:00
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:INTRODUCTION:Phosphoinositide 3-kinase (PI3K)-activated signalling has a critical role in the evolution of aggressive tumourigenesis and is therefore a prime target for anticancer therapy. Previously we have shown that the beta galactoside binding protein (betaGBP) cytokine, an antiproliferative molecule, induces funct...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2217
更新日期:2009-01-01 00:00:00
abstract:INTRODUCTION:Bcl-2 and Bcl-xL confer resistance to apoptosis, thereby reducing the effectiveness of chemotherapy. We examined the relationship between the expression of Bcl-2 and Bcl-xL and chemosensitivity of breast cancer cells, with the aim of developing specific targeted therapy. METHODS:Four human breast cancer c...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr1323
更新日期:2005-01-01 00:00:00
abstract:BACKGROUND:Breast cancer intrinsic molecular subtype (IMS) as classified by the expression-based PAM50 assay is considered a strong prognostic feature, even when controlled for by standard clinicopathological features such as age, grade, and nodal status, yet the molecular testing required to elucidate these subtypes i...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-020-1248-3
更新日期:2020-01-28 00:00:00
abstract:INTRODUCTION:Molecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors. METHODS:We performed quantitative reverse transcription PCR ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3421
更新日期:2013-05-11 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:The number of lymph nodes found to be involved in an axillary dissection is among the most powerful prognostic factors in breast cancer, but it is confounded by the number of lymph nodes that have been examined. We investigate an idea that has surfaced recently in the literature (since 1999), namely that t...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr934
更新日期:2004-01-01 00:00:00
abstract::Although the stroma in which carcinomas arise has been previously regarded as a bystander to the clonal expansion and acquisition of malignant characteristics of tumor cells, it is now generally acknowledged that stromal changes are required for the establishment of cancer. In the present article, we discuss three rec...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr972
更新日期:2005-01-01 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:Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia. The main challenge in the field, however, is the generation of therapeutic temperatures selectively in the whole tumor region. We aimed to improve magnetic hyperthermia of breast cancer by using innovative nanoparticles whi...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-015-0576-1
更新日期:2015-05-13 00:00:00
abstract:INTRODUCTION:The invasive, mesenchymal phenotype of CD44posCD24neg breast cancer cells has made them a promising target for eliminating the metastatic capacity of primary tumors. It has been previously demonstrated that CD44neg/lowCD24pos breast cancer cells lack the ability to give rise to their invasive CD44posCD24ne...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2449
更新日期:2009-01-01 00:00:00
abstract:INTRODUCTION:Bisphosphonates are inhibitors of osteoclast-mediated tumor-stimulated osteolysis, and they have become standard therapy for the management of bone metastases from breast cancer. These drugs can also directly induce growth inhibition and apoptosis of osteotropic cancer cells, including estrogen receptor-po...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr1363
更新日期:2006-01-01 00:00:00
abstract::The concept of 'targeted' therapies implies that such drugs only act on cells that specifically express the particular target, therefore giving rise to a low incidence of side effects. However, targeted therapies currently approved for the treatment of breast cancer have demonstrated a relatively high incidence of car...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr3142
更新日期:2012-06-19 00:00:00
abstract:BACKGROUND:A novel line of research suggests that eating at nighttime may have several metabolic consequences that are highly relevant to breast cancer. We investigated the association between nighttime eating habits after 10 p.m. and breast cancer in Hong Kong women. METHODS:A hospital-based case-control study was co...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-017-0821-x
更新日期:2017-03-17 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:INTRODUCTION:Breast cancer is genetically and clinically a heterogeneous disease. However, the exact contribution of different cell types and oncogenic mutations to this heterogeneity are not well understood. Recently, we discovered an interaction between Wnt and integrin-linked kinase (ILK) within the signaling cascad...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2592
更新日期:2010-01-01 00:00:00
abstract:INTRODUCTION:Reliable predictive and prognostic markers for routine diagnostic purposes are needed for breast cancer patients treated with neoadjuvant chemotherapy. We evaluated protein biomarkers in a cohort of 116 participants of the GeparDuo study on anthracycline/taxane-based neoadjuvant chemotherapy for operable b...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1186/bcr2363
更新日期:2009-01-01 00:00:00
abstract::Transforming growth factor-beta (TGF-beta) is a tumor suppressor, the function of which is compromised in many types of human cancer, including breast cancer. The tumor suppressive effects of TGF-beta are caused by potent inhibition of cell proliferation due to cell cycle arrest in the G1 phase. Such antiproliferative...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr42
更新日期:2000-01-01 00:00:00
abstract::ErbB (also termed HER) receptors are expressed in various tissues of epithelial, mesenchymal and neuronal origin, in which they are involved in the control of diverse biological processes such as proliferation, differentiation, migration and apoptosis. Furthermore, their deregulated expression has been implicated in m...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr327
更新日期:2001-01-01 00:00:00
abstract::Many women newly diagnosed with breast cancer and with a strong family history of breast cancer are referred to a family cancer service for genetic counselling and for consideration of genetic testing for germline mutations in cancer predisposition genes following completion of their cancer treatment. However, there i...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr2194
更新日期:2008-01-01 00:00:00
abstract:INTRODUCTION:The presence of tumor cells in the axillary lymph nodes is the most important prognostic factor in early stage breast cancer. However, the optimal method for sentinel lymph node (SLN) examination is still sought and currently many different protocols are employed. To examine two approaches for tumor cell d...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2922
更新日期:2011-08-04 00:00:00