Breast Cancer Research - Most accessed articles

MicroRNA let-7a suppresses breast cancer cell migration and invasion through down-regulation of C-C chemokine receptor type 7

Seok-Jun Kim — 2012-01-18T00:00:00Z

IntroductionC-C Chemokine receptor type7 (CCR7), plays an important role in chemotactic and metastatic responses in various cancers, including breast cancer. In this study, we demonstrated that microRNA Let-7a down-regulates CCR7 expression and directly influences the migration and invasion of breast cancer cells. Methods: We detected the expressions of CCR7, its ligand CCL21, and Let-7a in breast cancer cell lines and in breast cancer patient tissues. We used synthetic Let-7a oligo-nucleotides and inhibitor of Let-7a and transfection into respective MDA-MB-231 and MCF-7 breast cancer cells and performed the cell proliferation, cell migration and invasion assays. For the confirmed that 3-UTR of CCR7 is a direct target of Let-7a by employing luciferase assay for the reporter gene expressing Let-7a binding sites of CCR7 3-UTR. We also established in vivo invasion animal model using transparent zebrafish embryos to detect the effect of Let-7a on in vivo system. Results: First, we determined the over-expression of CCR7 in both and higher expression of CCL21 in malignant tissues than in their normal counterparts in breast cancer patients. We also detected the reverse-correlation in expression of CCR7 and Let-7a in breast cancer cell lines and breast cancer patient tissues. Synthetic Let-7a decreased breast cancer cell proliferation, migration and invasion as well as CCR7 protein expression in MDA-MB 231 cells. Inhibitor of Let-7a reversed these Let-7a effects on breast cancer cells in MCF-7 cells. It was confirmed that 3-UTR of CCR7 is a direct target of Let-7a by employing luciferase assay for the reporter gene expressing Let-7a binding sites of CCR7 3-UTR. Interestingly, we analyzed the in vivo invasion, which MDA-MB231 cells after synthetic Let-7a oligo-nucleotides transfection could not invade into the vessels in zebrafish embryos. Conclusions: These results suggest that targeting of CCL21-CCR7 signaling is a valid approach for breast cancer therapy and Let-7a directly binds the 3-UTR of CCR7 and blocks its protein expression, thereby suppressing migration and invasion of human breast cancer cells. Furthermore, this study underscores the therapeutic potential of Let-7a as an anti-tumor and anti-metastatic manager in breast cancer patients.

Long-term prognosis of breast cancer detected by mammography screening or other methods

Tiina Lehtimaki — 2011-12-28T00:00:00Z

IntroductionPrevious studies of breast cancer have shown that patients whose tumors are detected by mammography screening have a more favorable survival. Little is known, however, about the long-term prognostic impact of screen detection. The purpose of the current study was to compare breast cancer-specific long-term survival of patients whose tumors were detected in mammography screening compared with those whose tumors were detected by other methods. Methods: Breast cancer patients diagnosed within five specified geographical areas in Finland in 1991 and 1992 were identified (N = 2,936). Detailed clinical, treatment and outcome data, as well as tissue samples, were collected. Women with in situ carcinoma, distant metastases at the time of primary diagnosis and women who were not treated surgically were excluded. The main analyses were performed after excluding patients with other malignancy or contralateral breast cancer, followed by sensitivity analyses with different exclusion criteria. Median follow-up time was 15.4 years. Univariate and multivariate analyses of breast cancer-specific survival were performed. Results: Of patients included in the main analyses (n = 1,884), 22% (n = 408) of cancers were screen-detected and 78% (n = 1,476) were detected by other methods. Breast cancer-specific 15-year survival was 86% for patients with screen-detected cancer and 66% for patients diagnosed using other methods (P < 0.0001, HR = 2.91). Similar differences in survival were observed in women at screening age (50 to 69 years), as well as in clinically important subgroups, such as patients with small tumors (≤ 1 cm in diameter) and without nodal involvement (N0). Women with breast cancer diagnosed on the basis of screening mammography had a more favorable prognosis than those diagnosed outside screening programs, following adjustments according to patient age, tumor size, axillary lymph node status, histological grade and hormone receptor status. Significant differences in the risk of having future contralateral breast cancer according to method of detection were not observed. Conclusions: Breast cancer detected by mammography screening is an independent prognostic factor in breast cancer and is associated with a more favorable survival rate as well as in long-term follow-up.

Fatty breasts increase or decrease breast cancer risk?

Karla Kerlikowske — 2012-01-25T00:00:00Z

Few studies have investigated the association of non-dense area or fatty breasts in conjunction with breast density and breast cancer risk. Two articles in a recent issue of Breast Cancer Research investigate the role of absolute non-dense breast area measured on mammograms and find conflicting results: one article finds that non-dense breast area has a modest positive association with breast cancer risk, whereas the other finds that non-dense breast area has a strong protective effect to reduce breast cancer risk. Understanding the interplay of body mass index, menopause status, and measurement of non-dense breast area would help to clarify the contribution of non-dense breast area to breast cancer risk.

Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome

Grazia Arpino — 2004-02-17T00:00:00Z

IntroductionInvasive lobular carcinoma (ILC) comprises approximately 10% of breast cancers and appears to have a distinct biology. Because it is less common than infiltrating ductal carcinoma (IDC), few data have been reported that address the biologic features of ILC in the context of their clinical outcome. In the present study we undertook an extensive comparison of ILC and IDC using a large database to provide a more complete and reliable assessment of their biologic phenotypes and clinical behaviors. Methods: The clinical and biological features of 4140 patients with ILC were compared with those of 45,169 patients with IDC (not otherwise specified). The median follow-up period was 87 months. Results: In comparison with IDC, ILC was significantly more likely to occur in older patients, to be larger in size, to be estrogen and progesterone receptor positive, to have lower S-phase fraction, to be diploid, and to be HER-2, p53, and epidermal growth factor receptor negative. It was more common for ILC than for IDC to metastasize to the gastrointestinal tract and ovary. The incidence of contralateral breast cancer was higher for ILC patients than for IDC patients (20.9% versus 11.2%; P < 0.0001). Breast preservation was modestly less frequent in ILC patients than in IDC patients. The 5-year disease-free survival was 85.7% for ILC and 83.5% for IDC (P = 0.13). The 5-year overall survival was 85.6% for ILC and 84.1% for IDC (P = 0.64). Conclusion: Despite the fact that the biologic phenotype of ILC is quite favorable, these patients do not have better clinical outcomes than do patients with IDC. At present, management decisions should be based on individual patient and tumor biologic characteristics, and not on lobular histology.

Expression of stem cell and epithelial-mesenchymal transition markers in primary breast cancer patients with circulating tumor cells.

Sabine Kasimir-Bauer — 2012-01-20T00:00:00Z

IntroductionThe presence of circulating tumor cells (CTC) in breast cancer might be associated with stem cell like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors. Furthermore, to be able to disseminate and metastasize, CTC must be able to perform epithelial-mesenchymal transition (EMT). We studied the expression of three EMT markers and the stem cell marker ALDH1 in CTC from 502 primary breast cancer patients. Data were correlated with the presence of disseminated tumor cells (DTC) in the bone marrow (BM) and clinicopathological data of the patients. Methods: 2 x 5 ml blood was analyzed for CTC with the AdnaTest BreastCancer (AdnaGen AG) for the detection of EpCAM, MUC-1, HER2 and beta-Actin transcripts. The recovered c-DNA was additionally multiplex tested for three EMT markers [TWIST1, Akt2, PI3Kalpha] and separately for the tumor stem cell marker ALDH1. The identification of EMT markers was considered positive if at least one marker was detected in the sample. Two BM aspirates from all patients were analyzed for DTC by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Results: 97% of 30 healthy donor samples investigated were negative for EMT and 95% for ALDH1 transcripts, respectively. CTCs were detected in 97/502 (19%) patients. At least one of the EMT markers was expressed in 29% and ALDH1 was present in 14% of the samples, respectively. Interestingly, 5% of the ALDH1-positive and 18% of the EMT-positive patients were CTC-negative based on the cut-off level determined for CTC-positivity applying the AdnaTest BreastCancer. DTC in the BM were detected in 107/502 (21%) patients and no correlation was found between BM status and CTC positivity (p=0.41). The presence of CTC, EMT and ALDH1 expression was not correlated to any of the prognostic clinical markers. Conclusion: Our data indicate that (1) a subset of primary breast cancer patients shows EMT and stem cell characteristics and (2) the currently used detection methods for CTC are not efficient to identify a subtype of CTC which underwent EMT. (3) The clinical relevance on prognosis and therapy response has to be further evaluated in a prospective trial.

Epithelial-mesenchymal transition, cancer stem cells and treatment resistance

Bhuvanesh Dave — 2012-01-19T00:00:00Z

Breast cancer relapse, in a large number of patients, after initial response to standard of care therapy warrants development of novel therapies against recurrent and metastatic cancer. Cancer stem cells (CSCs), present in breast tumors while being intrinsically resistant to conventional therapy, have the ability to self renew and cause tumor recurrence. The residual tumors after therapy, with dramatic enrichment of the CSCs, have all the hallmarks of epithelial- mesenchymal transition (EMT). This review will focus on the link between EMT, CSCs and treatment resistance, since a better understanding of these interactions will allow us to effectively target the residual population after therapy.

Mouse models of breast cancer metastasis

Anna Fantozzi — 2006-07-26T00:00:00Z

Metastatic spread of cancer cells is the main cause of death of breast cancer patients, and elucidation of the molecular mechanisms underlying this process is a major focus in cancer research. The identification of appropriate therapeutic targets and proof-of-concept experimentation involves an increasing number of experimental mouse models, including spontaneous and chemically induced carcinogenesis, tumor transplantation, and transgenic and/or knockout mice. Here we give a progress report on how mouse models have contributed to our understanding of the molecular processes underlying breast cancer metastasis and on how such experimentation can open new avenues to the development of innovative cancer therapy.

Breast asymmetry and predisposition to breast cancer

Diane Scutt — 2006-03-20T00:00:00Z

IntroductionIt has been shown in our previous work that breast asymmetry is related to several of the known risk factors for breast cancer, and that patients with diagnosed breast cancer have more breast volume asymmetry, as measured from mammograms, than age-matched healthy women. Methods: In the present study, we compared the breast asymmetry of women who were free of breast disease at time of mammography, but who had subsequently developed breast cancer, with that of age-matched healthy controls who had remained disease-free to time of the present study. The study group consisted of 252 asymptomatic women who had normal mammography, but went on to develop breast cancer. The control group were 252 age-matched healthy controls whose mammograms were also normal and who remained free of cancer during the study period. Breast volume was calculated from the cranio-caudal mammograms for each group, and the relationships between asymmetry, established risk factors and the presence or absence of breast cancer were explored. Results: The group who went on to develop breast cancer had higher breast asymmetry than controls (absolute asymmetry odds ratio 1.50 per 100 ml, confidence interval (CI) 1.10, 2.04; relative asymmetry 1.09, CI 1.01, 1.18), increased incidence of family history of breast cancer, lower age at menarche, later menopause, later first pregnancies and a higher frequency of high risk breast parenchyma types. Conditional logistic regression analysis showed that breast asymmetry, height, family history of breast cancer, age at menarche, parenchyma type and menopausal status were significant independent predictors of breast cancer. When age at menopause was included in the model for the subgroup of post-menopausal women, absolute breast fluctuating asymmetry (FA) and relative breast FA remained significant effects. Conclusion: Breast asymmetry was greater in healthy women who later developed breast cancer than in women who did not.

Molecular profiling of patient-derived breast cancer xenografts

Fabien Reyal — 2012-01-16T00:00:00Z

IntroductionIdentification of new therapeutic agents for breast cancer (BC) requires preclinical models that reproduce the molecular characteristics of their respective clinical tumors. In this work, we analyzed the genomic and gene expression profiles of human BC xenografts and the corresponding patient tumors. Methods: Eighteen BC xenografts were obtained by grafting tumor fragments from patients into Swiss nude mice. Molecular characterization of patient tumors and xenografts was performed by DNA copy number analysis and gene expression analysis using Affymetrix Microarrays. Results: Comparison analysis showed that 14/18 pairs of tumors shared more than 56% of copy number alterations (CNA). Unsupervised hierarchical clustering analysis showed that 16/18 pairs segregated together, confirming the similarity between tumor pairs. Analysis of recurrent CNA changes between patient tumors and xenografts showed losses in 176 chromosomal regions and gains in 202 chromosomal regions. Gene expression profile analysis showed that less than 5% of genes had recurrent variations between patient tumors and their respective xenografts; these genes largely corresponded to human stromal compartment genes. Finally, analysis of different passages of the same tumor showed that sequential mouse-to-mouse tumor grafts did not affect genomic rearrangements or gene expression profiles, suggesting genetic stability of these models over time. Conclusions: This panel of human BC xenografts maintains the overall genomic and gene expression profile of the corresponding patient tumors and remains stable throughout sequential in vivo generations. The observed genomic profile and gene expression differences appear to be due to the loss of human stromal genes. These xenografts therefore represent a validated model for preclinical investigation of new therapeutic agents.

The microenvironment in breast cancer progression: biology and implications for treatment

Andrew Place — 2011-11-01T00:00:00Z

Breast cancer comprises a heterogeneous group of malignancies derived from the ductal epithelium. The microenvironment of these cancers is now recognized as a critical participant in tumor progression and therapeutic responses. Recent data demonstrate significant gene expression and epigenetic alterations in cells composing the microenvironment during disease progression, which can be explored as biomarkers and targets for therapy. Indeed, gene expression signatures derived from tumor stroma have been linked to clinical outcomes. There is increasing interest in translating our current understanding of the tumor microenvironment to the development of novel therapies.