Loss of E-cadherin is not a necessity for epithelial to mesenchymal transition in human breast cancer.

Epithelial to mesenchymal transition (EMT) is typically defined by the acquisition of a spindle cell morphology in combination with loss of E-cadherin and upregulation of mesenchymal markers. However, by studying E-cadherin inactivation in 38 human breast cancer cell lines, we noted that not all cell lines that had undergone EMT had concomitantly lost E-cadherin expression. We further investigated this discrepancy functionally and in clinical breast cancer specimens.

Correlation of breast cancer susceptibility loci with patient characteristics, metastasis-free survival, and mRNA expression of the nearest genes.

To understand the biology of low-risk breast cancer alleles, and to investigate whether these loci also contribute to disease progression that was once established, we examined the association of SNPs tagging the low-risk breast cancer loci in or near FGFR2, LSP1, MAP3K1, H19, TOX3, POU5F1P1, MYC, and 2q35, with clinical, pathological characteristics, prognosis, and mRNA expression of the nearest genes. Tumor DNA samples of 2,480 breast cancer patients were available. Out of this cohort, 1,290 patients with lymph-node negative disease who did not receive adjuvant systemic therapy, the SNP status was associated with metastasis-free survival (MFS).

Gene expression profiling assigns CHEK2 1100delC breast cancers to the luminal intrinsic subtypes.

CHEK2 1100delC is a moderate-risk cancer susceptibility allele that confers a high breast cancer risk in a polygenic setting. Gene expression profiling of CHEK2 1100delC breast cancers may reveal clues to the nature of the polygenic CHEK2 model and its genes involved. Here, we report global gene expression profiles of a cohort of 155 familial breast cancers, including 26 CHEK2 1100delC mutant tumors.

Randomized phase II study comparing efficacy and safety of combination-therapy trastuzumab and docetaxel vs. sequential therapy of trastuzumab followed by docetaxel alone at progression as first-line chemotherapy in patients with HER2+ metastatic breast cancer: HERTAX trial.

Background: Because chemotherapy for metastatic breast cancer (MBC) is associated with relevant toxicity, sequential monotherapy trastuzumab followed by cytotoxic therapy at disease progression might be an attractive approach.

Methods: In a multicenter phase II trial, 101 patients with overexpression of human epidermal growth factor receptor 2 (HER2(+)) MBC were randomized between combination-therapy trastuzumab (Herceptin) plus docetaxel (H+D) and sequential therapy of single-agent trastuzumab followed at disease progression by docetaxel alone (H→D) as first-line chemotherapy for metastatic disease. The primary endpoint was progression-free survival (PFS) after completed sequential or combination therapy.

BRCA1-associated breast cancers present differently from BRCA2-associated and familial cases: long-term follow-up of the Dutch MRISC Screening Study.

Purpose: The Dutch MRI Screening Study on early detection of hereditary breast cancer started in 1999. We evaluated the long-term results including separate analyses of BRCA1 and BRCA2 mutation carriers and first results on survival.

Patients And Methods: Women with higher than 15% cumulative lifetime risk (CLTR) of breast cancer were screened with biannual clinical breast examination and annual mammography and magnetic resonance imaging (MRI).

Increased MUTYH mutation frequency among Dutch families with breast cancer and colorectal cancer.

Homozygous and compound heterozygous MUTYH mutations predispose for MUTYH-associated polyposis (MAP). The clinical phenotype of MAP is characterised by the multiple colorectal adenomas and colorectal carcinoma. We previously found that female MAP patients may also have an increased risk for breast cancer.

Association of rare MSH6 variants with familial breast cancer.

Germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 predispose to Lynch syndrome (also known as hereditary non-polyposis colorectal cancer). Recently, we have shown that the CHEK2 1100delC mutation also is associated with Lynch syndrome/Lynch syndrome-associated families albeit in a polygenic setting. Two of the ten CHEK2 1100delC positive Lynch syndrome families additionally carried a pathogenic MLH1 or MSH6 mutation, suggesting that mutations in mismatch repair genes may be involved in CHEK2 1100delC-associated cancer phenotypes.

Assessment of false-negative cases of breast MR imaging in women with a familial or genetic predisposition.

In order to assess the characteristics of malignant breast lesions those were not detected during screening by MR imaging. In the Dutch MRI screening study(MRISC), a non-randomized prospective multicenter study,women with high familial risk or a genetic predisposition for breast cancer were screened once a year by mammography and MRI and every 6 months with a clinical breast examination (CBE). The false-negative MR examinations were subject of this study and were retrospectively reviewed by two experienced radiologists.

Four human breast cancer cell lines with biallelic inactivating alpha-catenin gene mutations.

Mutations of E-cadherin have been identified in half of lobular breast cancers and diffuse-type gastric cancers, two tumor subtypes with remarkably similar pathological appearances including small rounded cells with scant cytoplasm and a diffuse growth pattern. A causal role for E-cadherin gene mutations in the lobular breast cancer phenotype was recently demonstrated in E-cadherin knock-out mice. These observations suggested that another gene in the E-cadherin tumor suppressor pathway might be mutated in lobular breast cancers with wild-type E-cadherin genes.

Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines.

Breast cancer has for long been recognized as a highly diverse tumor group, but the underlying genetic basis has been elusive. Here, we report an extensive molecular characterization of a collection of 41 human breast cancer cell lines. Protein and gene expression analyses indicated that the collection of breast cancer cell lines has retained most, if not all, molecular characteristics that are typical for clinical breast cancers.

Sensitivity to first-line chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers.

Purpose: Preclinical as well as a few small retrospective, neoadjuvant studies suggest that breast cancer (cells) without functional BRCA1 or BRCA2 protein have an increased sensitivity to some chemotherapeutic agents causing double-strand DNA breaks. In this study we assessed the sensitivity to standard first-line chemotherapy of metastatic BRCA1/2-associated breast cancer, compared with sporadic breast cancer patients.

Patients And Methods: From the Family Cancer Clinic database, we selected 93 BRCA1- and 28 BRCA2-associated breast cancer patients treated with chemotherapy for metastatic disease before January 1, 2007.

Standard psychological consultations and follow up for women at increased risk of hereditary breast cancer considering prophylactic mastectomy.

Background: Women at increased (genetic) risk of breast cancer have to weigh the personal pros and cons of prophylactic mastectomy (PM) as an option to reduce their cancer risk. So far, no routine referral to a psychologist has been investigated for women considering PM. Aim of this study was to asses: 1) the acceptance of the offer of a standard psychological consultation as part of pre-surgical decision-making in high-risk women, 2) reasons for PM and reasons for postponing it, 3) the need for additional psychological interventions, and factors associated, and 4) the frequency of psychiatric/psychological treatment history.

Copy number alterations that predict metastatic capability of human breast cancer.

We have analyzed the DNA copy numbers for over 100,000 single-nucleotide polymorphism loci across the human genome in genomic DNA from 313 lymph node-negative primary breast tumors for which genome-wide gene expression data were also available. Combining these two data sets allowed us to identify the genomic loci and their mapped genes, having high correlation with distant metastasis. An estimation of the likely response based on published predictive signatures was performed in the identified prognostic subgroups defined by gene expression and DNA copy number data.

Roles of radiotherapy and chemotherapy in the development of contralateral breast cancer.

Purpose: Few studies have examined whether modern radiotherapy and chemotherapy affect the risk of contralateral breast cancer (CBC), and results are inconclusive.

Patients And Methods: We assessed long-term risk of CBC in a predominantly young breast cancer (BC) population (n = 7,221), focusing on the effects of radiation dose, chemotherapy, and family history of BC. Risk of CBC was evaluated using Cox proportional hazards regression models.

Association of an extracellular matrix gene cluster with breast cancer prognosis and endocrine therapy response.

Purpose: We previously discovered an extracellular matrix (ECM) gene cluster associated with resistance to first-line tamoxifen therapy of patients with metastatic breast cancer. In this study, we determined whether the six individual ECM genes [collagen 1A1 (COL1A1), fibronectin 1 (FN1), lysyl oxidase (LOX), secreted protein acidic cysteine-rich (SPARC), tissue inhibitor of metalloproteinase 3 (TIMP3), and tenascin C (TNC)] were associated with treatment response, prognosis, or both.

Experimental Design: In 1,286 primary breast tumors, mRNA expression (quantitative real-time PCR) was related to clinicopathologic factors and disease outcome in univariate and multivariate analysis including traditional factors.

CHEK2 1100delC and male breast cancer in the Netherlands.

Mutations in the breast cancer susceptibility genes BRCA1, BRCA2, and CHEK2 are known risk factors for female breast cancer. Mutations in BRCA1 and BRCA2 also are associated with male breast cancer (MBC). Similarly, it had been suggested in the original CHEK2 identification report that the CHEK2 1100delC mutation confers an increased risk for MBC.

Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer.

In this study, we quantified 249 mature micro-RNA (miRNA) transcripts in estrogen receptor-positive (ER(+)) primary breast tumors of patients with lymph node-negative (LNN) disease to identify miRNAs associated with metastatic capability. In addition, the prognostic value of the candidate miRNAs was determined in ER(-)/LNN breast cancer. Unsupervised analysis in a prescreening set of 38 patients identified three subgroups predominantly driven by three miRNA signatures: an ER-driven luminal B-associated miRNA signature, a stromal miRNA signature, and an overexpressed miRNA cluster located on chromosome 19q23, but these intrinsic miRNA signatures were not associated with tumor aggressiveness.

CHEK2 1100delC is a susceptibility allele for HNPCC-related colorectal cancer.

Purpose: The pathogenic CHEK2 1100delC variant is firmly established as a breast cancer susceptibility allele. Dutch CHEK2 1100delC breast cancer families frequently also include colorectal cancer cases, and the variant is particularly prevalent among breast cancer families with hereditary breast and colorectal cancer. Yet, it is still unclear whether CHEK2 1100delC also confers a colorectal cancer risk independent of its breast cancer risk.

A family history of breast cancer will not predict female early onset breast cancer in a population-based setting.

Background: An increased risk of breast cancer for relatives of breast cancer patients has been demonstrated in many studies, and having a relative diagnosed with breast cancer at an early age is an indication for breast cancer screening. This indication has been derived from estimates based on data from cancer-prone families or from BRCA1/2 mutation families, and might be biased because BRCA1/2 mutations explain only a small proportion of the familial clustering of breast cancer. The aim of the current study was to determine the predictive value of a family history of cancer with regard to early onset of female breast cancer in a population based setting.

Downregulation of SIAH2, an ubiquitin E3 ligase, is associated with resistance to endocrine therapy in breast cancer.

Purpose: In our microarray analysis we observed that Seven-in-Absentia Homolog 2 (SIAH2) levels were low in estrogen receptor (ER) positive breast tumors of patients resistant to first-line tamoxifen therapy. The aim of this study was to evaluate SIAH2 for its (a) predictive/prognostic value, and (b) functional role in endocrine therapy resistance.

Patients And Methods: SIAH2 expression was measured with quantitative Real-Time-PCR (qRT-PCR) in 1205 primary breast tumor specimens and related to disease outcome.

The use of genomic tools for the molecular understanding of breast cancer and to guide personalized medicine.

The use of gene-expression microarray analysis to assess the expression levels of all the genes in the genome has tremendous potential. Important information has been obtained about many disease processes, particularly in classifying tumors in different subtypes and risk groups. Combining gene-expression data with other genomic information and the use of sophisticated bioinformatic tools enables the discovery of potential new targets for treatment, and is helpful for high-throughput drug screening and for designing new classes of drugs for targeted therapy.

Subtypes of breast cancer show preferential site of relapse.

We explored whether the five previously reported molecular subtypes in breast cancer show a preference for organ-specific relapse and searched for molecular pathways involved. The "intrinsic" gene list describing the subtypes was used to classify 344 primary breast tumors of lymph node-negative patients. Fisher exact tests were used to determine the association between a tumor subtype and a particular site of distant relapse in these patients who only received local treatment.

Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies.