Adipocyte-derived IL-6 and leptin promote breast Cancer metastasis via upregulation of Lysyl Hydroxylase-2 expression

Background

Adipocytes make up the major component of breast tissue, accounting for 90% of stromal tissue. Thus, the crosstalk between adipocytes and breast cancer cells may play a critical role in cancer progression. Adipocyte-breast cancer interactions have been considered important for the promotion of breast cancer metastasis. However, the specific mechanisms underlying these interactions are unclear. In this study, we investigated the mechanisms of adipocyte-mediated breast cancer metastasis.

Methods

Breast cancer cells were cocultured with mature adipocytes for migration and 3D matrix invasion assays. Next, lentivirus-mediated loss-of-function experiments were used to explore the function of lysyl hydroxylase (PLOD2) in breast cancer migration and adipocyte-dependent migration of breast cancer cells. The role of PLOD2 in breast cancer metastasis was further confirmed using orthotopic mammary fat pad xenografts in vivo. Clinical samples were used to confirm that PLOD2 expression is increased in tumor tissue and is associated with poor prognosis of breast cancer patients. Cells were treated with cytokines and pharmacological inhibitors in order to verify which adipokines were responsible for activation of PLOD2 expression and which signaling pathways were activated in vitro.

Results

Gene expression profiling and Western blotting analyses revealed that PLOD2 was upregulated in breast cancer cells following coculture with adipocytes; this process was accompanied by enhanced breast cancer cell migration and invasion. Loss-of-function studies indicated that PLOD2 knockdown suppressed cell migration and disrupted the formation of actin stress fibers in breast cancer cells and abrogated the migration induced by following coculture with adipocytes. Moreover, experiments performed in orthotopic mammary fat pad xenografts showed that PLOD2 knockdown could reduce metastasis to the lung and liver. Further, high PLOD2 expression correlated with poor prognosis of breast cancer patients. Mechanistically, adipocyte-derived interleukin-6 (IL-6) and leptin may facilitate PLOD2 upregulation in breast cancer cells and promote breast cancer metastasis in tail vein metastasis assays. Further investigation revealed that adipocyte-derived IL-6 and leptin promoted PLOD2 expression through activation of the JAK/STAT3 and PI3K/AKT signaling pathways.

Conclusions

Our study reveals that adipocyte-derived IL-6 and leptin promote PLOD2 expression by activating the JAK/STAT3 and PI3K/AKT signaling pathways, thus promoting breast cancer metastasis.

     

An isomiR expression panel based novel breast cancer classification approach using improved mutual information

Background

Gene expression-based profiling has been used to identify biomarkers for different breast cancer subtypes. However, this technique has many limitations. IsomiRs are isoforms of miRNAs that have critical roles in many biological processes and have been successfully used to distinguish various cancer types. Biomarker isomiRs for identifying different breast cancer subtypes has not been investigated. For the first time, we aim to show that isomiRs are better performing biomarkers and use them to explain molecular differences between breast cancer subtypes.

Results

In this study, a novel method is proposed to identify specific isomiRs that faithfully classify breast cancer subtypes. First, as a null hypothesis method we removed the lowly expressed isomiRs from small sequencing data generated from diverse breast cancers types. Second, we developed an improved mutual information-based feature selection method to calculate the weight of each isomiR expression. The weight of isomiR measures the importance of a given isomiR in classifying breast cancer subtypes. The improved mutual information enables to apply the dataset in which the feature is continuous data and label is discrete data; whereby, the traditional mutual information cannot be applied in this dataset. Finally, the support vector machine (SVM) classifier is applied to find isomiR biomarkers for subtyping.

Conclusions

Here we demonstrate that isomiRs can be used as biomarkers in the identification of different breast cancer subtypes, and in addition, they may provide new insights into the diverse molecular mechanisms of breast cancers. We have also shown that the classification of different subtypes of breast cancer based on isomiRs expression is more effective than using published gene expression profiling. The proposed method provides a better performance outcome than Fisher method and Hellinger method for discovering biomarkers to distinguish different breast cancer subtypes. This novel technique could be directly applied to identify biomarkers in other diseases.

     

Clinical practice guidelines for the care and treatment of breast cancer: 14. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer

Objective

To provide information and recommendations to women with a previous diagnosis of breast cancer and their physicians regarding hormone replacement therapy (HRT).

Outcomes

Control of menopausal symptoms, quality of life, prevention of osteoporosis, prevention of cardiovascular disease, risk of recurrence of breast cancer, risk of death from breast cancer.

Evidence

Systematic review of English-language literature published from January 1990 to July 2001 retrieved from MEDLINE and CANCERLIT.

Recommendations

· Routine use of HRT (either estrogen alone or estrogen plus progesterone) is not recommended for women who have had breast cancer. Randomized controlled trials are required to guide recommendations for this group of women. Women who have had breast cancer are at risk of recurrence and contralateral breast cancer. The potential effect of HRT on these outcomes in women with breast cancer has not been determined in methodologically sound studies. However, in animal and in vitro studies, the development and growth of breast cancer is known to be estrogen dependent. Given the demonstrated increased risk of breast cancer associated with HRT in women without a diagnosis of breast cancer, it is possible that the risk of recurrence and contralateral breast cancer associated with HRT in women with breast cancer could be of a similar magnitude. · Postmenopausal women with a previous diagnosis of breast cancer who request HRT should be encouraged to consider alternatives to HRT. If menopausal symptoms are particularly troublesome and do not respond to alternative approaches, a well-informed woman may choose to use HRT to control these symptoms after discussing the risks with her physician. In these circumstances, both the dose and the duration of treatment should be minimized.

Validation

Internal validation within the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer; no external validation.

Sponsor

The steering committee was convened by Health Canada.

Completion date

October 2001.Hormone replacement therapy (HRT) connotes treatment with either estrogen alone or estrogen with progesterone in postmenopausal women. Menopausal symptoms, such as hot flashes and vaginal dryness, and the potential long-term effects of estrogen deprivation are a concern to women with breast cancer, particularly those in whom menopause develops early as a result of adjuvant chemotherapy.Traditionally, the use of HRT has been contraindicated in women with breast cancer because of the notion that the development and growth of breast cancer is estrogen dependent and that the introduction of HRT may increase the risk of breast cancer recurrence. The focus of this guideline is on whether it is safe to give HRT to women with breast cancer.     

The interplay between glucose and fatty acids on tube formation and fatty acid uptake in the first trimester trophoblast cells,HTR8/SVneo

Anillin (ANLN), an actin-binding protein, is required for cytokinesis. Recently, ANLN has been identified as a biomarker in diverse human cancers; however, the precise role of ANLN in breast cancer remains unclear. In this study, we firstly detected the expression of ANLN in 71 patients with breast cancer by immunohistochemistry, and found ANLN was highly expressed in breast cancer tissues. To evaluate the function of ANLN in breast cancer cells, we employed lentivirus-mediated RNA interference to knock down ANLN expression in two human breast cancer cell lines, MDA-MB-231, and ZR-75-30. Knockdown of ANLN remarkably inhibited the proliferation rate and colony formation ability of both breast cancer cell lines. Moreover, flow cytometry analysis showed that depletion of ANLN in MDA-MB-231 cells blocked the cell cycle progression, with more cells delayed at G₂/M phase, due to phosphorylation of Cdc2 and suppression of Cyclin D1. Furthermore, knockdown of ANLN strongly suppressed the migration of breast cancer cells, strengthening the evidence that ANLN could be involved in breast cancer progression. Our results may suggest ANLN as a potential target candidate in breast cancer.     

Comorbid Diseases Interact with Breast Cancer to Affect Mortality in the First Year after Diagnosis—A Danish Nationwide Matched Cohort Study

Background

Survival of breast cancer patients with comorbidity, compared to those without comorbidity, has been well characterized. The interaction between comorbid diseases and breast cancer, however, has not been well-studied.

Methods

From Danish nationwide medical registries, we identified all breast cancer patients between 45 and 85 years of age diagnosed from 1994 to 2008. Women without breast cancer were matched to the breast cancer patients on specific comorbid diseases included in the Charlson comorbidity Index (CCI). Interaction contrasts were calculated as a measure of synergistic effect on mortality between comorbidity and breast cancer.

Results

The study included 47,904 breast cancer patients and 237,938 matched comparison women. In the first year, the strongest interaction between comorbidity and breast cancer was observed in breast cancer patients with a CCI score of ≥4, which accounted for 29 deaths per 1000 person-years. Among individual comorbidities, dementia interacted strongly with breast cancer and accounted for 148 deaths per 1000 person-years within one year of follow-up. There was little interaction between comorbidity and breast cancer during one to five years of follow-up.

Conclusions

There was substantial interaction between comorbid diseases and breast cancer, affecting mortality. Successful treatment of the comorbid diseases or the breast cancer can delay mortality caused by this interaction in breast cancer patients.     

Familial breast cancer in Costa Rica: an initial approach

Cancer is a worldwide problem because of its high rates of incidence and associated mortality. By 2000, more than 6.2 million people died from this illness worldwide. Among all types of cancer, breast cancer is one of the most studied. Each year, one million new cases are diagnosed around the world. We can classify breast cancer into two main kinds: sporadic cases and those which are a product of inherited genetic alterations. Approximately 5-10% of breast cancer cases are the result of inherited mutations, or alterations in breast cancer susceptibility genes, BRCA1 and BRCA2. Like other countries, Costa Rica possesses high rates of incidence and mortality for breast cancer. According to the "Registro Nacional de Tumores" (National Office of Tumor Records), in 2000 breast cancer had the highest rate of incidence and in 2002 it had the highest rate of mortality in comparison to other types of cancer. For this reason and the generalized lack of knowledge in the field we conducted an epidemiological research on breast cancer patients from Hospital San Juan de Dios, San José, Costa Rica, to find families with a history of breast cancer, and to determine the occurrence of familial cases within the population studied. So far, we have found 23 families, within which we discovered very informative cases that have rendered the identification of a pattern of inheritance. These findings allow us to announce that in Costa Rica there are several cases of inherited breast cancer and that we need more research is needed to improve the prevention, control, and treatment of this disease.     

The oestrogen paradox: a hypothesis

Epidemiological and observational studies suggest that oestrogens, when used as hormonal therapy in post-menopausal women, can increase the risk of breast cancer if used long term. However, more recent data suggest that short-term use in sub-groups of post-menopausal women significantly decreases the risk of breast cancer. This beneficial effect is also observed when high-dose oestrogen is administered to post-menopausal women with breast cancer to cause tumour regression, a phenomenon which commonly occurs. We consider these divergent responses to oestrogen to represent a "paradox". Data from our own and other investigative groups suggest a hypothesis to explain this paradox. Deprivation of oestradiol in model systems causes cells to adapt and to undergo apoptosis in response to oestrogen. This occurs through the Fas/Fas ligand death receptor pathway and through alterations in apoptotic mechanisms mediated by mitochondria. This process of programmed cell death may explain the regression of established breast cancer with oestrogen administration and the diminution in the rate of new breast cancer diagnoses recently reported. Our hypothesis is based upon pathological data indicating the presence of a "reservoir" of undiagnosed breast cancer in the population of women who would be starting on oestrogens as menopausal hormonal therapy. The long-term increased risk of breast cancer may then reflect different mechanisms. Oestrogens can cause mutations through enhancement of the rate of cell division and concomitantly the error rate in DNA replication. In addition, oestrogens can be metabolised to directly genotoxic compounds. These carcinogenic processes take much longer, since a number of mutations must accumulate before resulting in breast cancer. These hypotheses regarding oestrogen-induced apoptosis in the short term and carcinogenesis in the long term now require rigorous verification but would serve to explain the "oestrogen paradox".     

N-3 Polyunsaturated Fatty Acids of Marine Origin and Multifocality in Human Breast Cancer

Objective

The microenvironment of breast epithelial tissue may contribute to the clinical expression of breast cancer. Breast epithelial tissue, whether healthy or tumoral, is directly in contact with fat cells, which in turn could influence tumor multifocality. In this pilot study we investigated whether the fatty acid composition of breast adipose tissue differed according to breast cancer focality.

Methods

Twenty-three consecutive women presenting with non-metastatic breast cancer underwent breast-imaging procedures including Magnetic Resonance Imaging prior to treatment. Breast adipose tissue specimens were collected during breast surgery. We established a biochemical profile of adipose tissue fatty acids by gas chromatography. We assessed whether there were differences according to breast cancer focality.

Results

We found that decreased levels in breast adipose tissue of docosahexaenoic and eicosapentaenoic acids, the two main polyunsaturated n-3 fatty acids of marine origin, were associated with multifocality.

Discussion

These differences in lipid content may contribute to mechanisms through which peritumoral adipose tissue fuels breast cancer multifocality.     

Preventive health care, 1999 update: 3. Follow-up after breast cancer

OBJECTIVE: To make recommendations to physicians who provide follow-up care for women who have been treated for early-stage breast cancer. OPTIONS: Combination of blood tests, bone scans, liver echography and chest radiography for detection of distant disease; physical examination with or without mammography for detection of contralateral breast cancer; and physical examination with or without mammography for detection of ipsilateral recurrent disease after breast-conserving therapy. OUTCOMES: Survival, disease recurrence and quality-of-life measures for distant disease, local recurrence of disease and disease in the contralateral breast. EVIDENCE: A MEDLINE search for relevant articles published between January 1966 and January 1998 with the MeSH terms "breast neoplasms" and "neoplasm recurrence" (local and distant) with limits to "human" was done. A subsequent MEDLINE search using the MeSH terms "breast neoplasms," "neoplasm recurrence," "local/diagnosis" and "mammography" was done to address issues of mammography. The literature search was reviewed by a medical librarian and 2 breast cancer specialists to ensure completeness. BENEFITS, HARMS AND COSTS: Breast cancer is the most common cancer in Canadian women and is the second leading cause of death after lung cancer. Even with early-stage breast cancer, recurrence after treatment for primary breast cancer is frequent. Traditionally, follow-up has been felt to facilitate early detection and improve survival. Randomized controlled trials (RCTs) have shown that routine screening (blood tests and diagnostic imaging) for distant disease does not alter survival or quality of life over routine physical examination. In an underpowered secondary analysis of RCT data, the detection of contralateral breast cancer did not affect survival. However, there have been no RCTs examining the role of mammography and physical examination and their effect on survival in the detection of contralateral breast cancer. The sensitivity and specificity of mammography after local excision and radiotherapy is unknown. There have been no RCTs examining the role of mammography or physical examination, or both, and their effect on survival in the detection of ipsilateral breast recurrence. VALUES: The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care. A high value was placed on interventions that changed survival. When evidence was available, high value was also placed on interventions that affected quality of life. RECOMMENDATIONS: There is good evidence not to include blood work and diagnostic imaging as part of screening for distant disease (grade E recommendation). There is no evidence to suggest that mammography decreases mortality by detecting ipsilateral disease in the conservatively treated breast; however, there is indirect evidence that it may be beneficial (grade C recommendation). There is no direct evidence to suggest that physical examination or mammography, or both, should be used to detect contralateral breast cancer; however, there is indirect evidence that it may be beneficial (grade C recommendation). VALIDATION: The findings of this analysis were reviewed through an iterative process by the members of the Canadian Task Force on Preventive Health Care.     

Breast cancer in the personal genomics era

Breast cancer is a heterogeneous disease with a complex etiology that develops from different cellular lineages, progresses along multiple molecular pathways, and demonstrates wide variability in response to treatment. The "standard of care" approach to breast cancer treatment in which all patients receive similar interventions is rapidly being replaced by personalized medicine, based on molecular characteristics of individual patients. Both inherited and somatic genomic variation is providing useful information for customizing treatment regimens for breast cancer to maximize efficacy and minimize adverse side effects. In this article, we review (1) hereditary breast cancer and current use of inherited susceptibility genes in patient management; (2) the potential of newly-identified breast cancer-susceptibility variants for improving risk assessment; (3) advantages and disadvantages of direct-to-consumer testing; (4) molecular characterization of sporadic breast cancer through immunohistochemistry and gene expression profiling and opportunities for personalized prognostics; and (5) pharmacogenomic influences on the effectiveness of current breast cancer treatments. Molecular genomics has the potential to revolutionize clinical practice and improve the lives of women with breast cancer.     

Comprehensive quantitative lipidomic approach to investigate serum phospholipid alterations in breast cancer

Introduction

Globally, breast cancer is the most common cancer in women and ranks second most common cause of cancer related mortality. Although efforts are made by researchers in molecular characterization of breast cancer using “-OMIC’S” approaches, limited work has explored to understand the phospholipid alterations in breast cancer.

Objectives

This study aims to explore five classes of serum phospholipid alterations in breast cancer towards discrimination of breast cancer from benign and healthy controls.

Methods

Twenty eight each of breast cancer patients and age-matched benign and healthy control serum samples were used to identify alterations of phospholipids using liquid chromatography-multiple reaction monitoring-mass spectrometry. Both multivariate and univariate statistical analyses were applied to investigate breast cancer associated phospholipid alterations. Differentially expressed phospholipid species were further confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results

Among the identified and quantified 200 phospholipids, 25 phospholipids were found to be statistically significant (VIP > 1.4 and ANOVA p < 0.05) in the serum of women with breast cancer when compared with benign and healthy controls. Comparison of serum phospholipids of breast cancer patients and healthy controls revealed 12 phospholipids were found to be differentially expressed in which six were up-regulated and six were down-regulated. While comparative analysis of breast cancer serum against benign showed an increased concentration of six phospholipids in breast cancer samples. Further, significantly altered phospholipids were structurally characterized by enhanced product ion scanning.

Conclusion

Our results demonstrate that some of the differentially regulated phospholipids identified in our study such as PE (14:1/16:0), PC (18:0/18:0), LPE 14:0, PE (20:0/22:2) could be a panel of potential signature which can discriminate breast cancer from benign and healthy controls. These findings also provide insight into lipidomic information that can be used for monitoring of breast cancer progression.

     

Risk of breast cancer in women with history of benign disease of the breast.

A consecutive series of 791 women who had attended diagnostic breast clinics during 1967-70 and been found to be free of malignant disease were later traced to determine their subsequent incidence of breast cancer. Of the 770 (97%) successfully traced, 22 had developed breast cancer. Based on data from the Welsh Cancer Registry only eight cases of breast cancer had been expected, so that the excess risk for the group was 2.7. The increased risk occurred in all age groups and in women deemed "essentially normal" as well as in those who had had a pathological abnormality. The risk was increased when epithelial hyperplasia was present. No excess mortality from breast cancer was apparent, but follow up was short. More breast symptoms were experienced and more biopsies performed than expected in this group of women. Women with a past history of benign breast disease have a slightly increased risk of breast cancer. Selective screening of these women, however, may be uneconomic and a cause of groundless anxiety.     

Breast cancer cells induce cancer-associated fibroblasts to secrete hepatocyte growth factor to enhance breast tumorigenesis

It has been well documented that microenvironment consisting of stroma affects breast cancer progression. However, the mechanisms by which cancer cells and fibroblasts, the major cell type in stroma, interact with each other during tumor development remains to be elucidated. Here, we show that the human cancer-associated fibroblasts (CAFs) had higher activity in enhancing breast tumorigenecity compared to the normal tissue-associated fibroblasts (NAFs) isolated from the same patients. The expression level of hepatocyte growth factor (HGF) in these fibroblasts was positively correlated with their ability to enhance breast tumorigenesis in mice. Deprivation of HGF using a neutralizing antibody reduced CAF-mediated colony formation of human breast cancer cells, indicating that CAFs enhanced cancer cell colony formation mainly through HGF secretion. Co-culture with human breast cancer MDA-MB-468 cells in a transwell system enhanced NAFs to secret HGF as well as promote tumorigenecity. The newly gained ability of these "educated" NAFs became irreversible after continuing this process till fourth passage. These results suggested that breast cancer cells could alter the nature of its surrounding fibroblasts to secrete HGF to support its own progression through paracrine signaling.     

Exposure to Bovine Leukemia Virus Is Associated with Breast Cancer: A Case-Control Study

Background

Age, reproductive history, hormones, genetics, and lifestyle are known risk factors for breast cancer, but the agents that initiate cellular changes from normal to malignant are not understood. We previously detected bovine leukemia virus (BLV), a common oncogenic virus of cattle, in the breast epithelium of humans. The objective of this study was to determine whether the presence of BLV DNA in human mammary epithelium is associated with breast cancer.

Methods

This was a case-control study of archival formalin fixed paraffin embedded breast tissues from 239 donors, received 2002–2008 from the Cooperative Human Tissue Network. Case definition as breast cancer versus normal (women with no history of breast cancer) was established through medical records and examination of tissues by an anatomical pathologist. Breast exposure to BLV was determined by in situ-PCR detection of a biomarker, BLV DNA, localized within mammary epithelium.

Results

The frequency of BLV DNA in mammary epithelium from women with breast cancer (59%) was significantly higher than in normal controls (29%) (multiply- adjusted odds ratio = 3.07, confidence interval = 1.66–5.69, p = .0004, attributable risk = 37%). In women with premalignant breast changes the frequency of BLV DNA was intermediate (38%) between that of women with breast cancer and normal controls (p for trend < .001).

Conclusions

Among the specimens in this study, the presence of amplified BLV DNA was significantly associated with breast cancer. The odds ratio magnitude was comparable to those of well-established breast cancer risk factors related to reproductive history, hormones, and lifestyle and was exceeded only by risk factors related to genetics (familial breast cancer), high dose ionizing radiation, and age. These findings have the potential for primary and secondary prevention of breast cancer.     

Breast Cancer Attributable Costs in Germany: A Top-Down Approach Based on Sickness Funds Data

Background

Breast cancer is the leading cause of death from cancer among women in Germany. Despite its clinical and economic relevance, no attributable costs for breast cancer have been reported for Germany so far. The objective of this study is to estimate age-specific breast cancer attributable health expenditures for Germany.

Methods

Sickness fund data from 1999 representing about 26 million insured (i.e. 32% of the total German population) have been analysed using generalized additive models and the error propagation law. Costs have been inflated to 2010.

Results

Breast cancer attributable costs decreased with age. Among breast cancer patients aged 30–45 years, about 90% of all health expenditures were due to breast cancer, whereas in breast cancer patients aged 80–90 years, about 50% were due to breast cancer. Breast cancer attributable costs amounted to about €9,000 annually for patients below 55 years of age and declined to about €3,000 in 90-year-old breast cancer patients.

Conclusion

This analysis provides estimates of attributable breast cancer costs in Germany. Compared with the international literature, the estimates were plausible but had a tendency to underestimate breast cancer attributable costs.     

BCAR3 Regulates Src/p130Cas Association, Src Kinase Activity, and Breast Cancer Adhesion Signaling

The nonreceptor protein-tyrosine kinase c-Src is frequently overexpressed and/or activated in a variety of cancers, including those of the breast. Several heterologous binding partners of c-Src have been shown to regulate its catalytic activity by relieving intramolecular autoinhibitory interactions. One such protein, p130^Cas (Cas), is expressed at high levels in both breast cancer cell lines and breast tumors, providing a potential mechanism for c-Src activation in breast cancers. The Cas-binding protein BCAR3 (breast cancer antiestrogen resistance-3) is expressed at high levels in invasive breast cancer cell lines, and this molecule has previously been shown to coordinate with Cas to increase c-Src activity in COS-1 cells. In this study, we show for the first time using gain- and loss-of-function approaches that BCAR3 regulates c-Src activity in the endogenous setting of breast cancer cells. We further show that BCAR3 regulates the interaction between Cas and c-Src, both qualitatively as well as quantitatively. Finally, we present evidence that the coordinated activity of these proteins contributes to breast cancer cell adhesion signaling and spreading. Based on these data, we propose that the c-Src/Cas/BCAR3 signaling axis is a prominent regulator of c-Src activity, which in turn controls cell behaviors that lead to aggressive and invasive breast tumor phenotypes.     

CCAAT/Enhancer binding protein delta (c/EBPdelta) regulation and expression in human mammary epithelial cells: I. "Loss of function" alterations in the c/EBPdelta growth inhibitory pathway in breast cancer cell lines

"Loss of function" alterations in growth inhibitory signal transduction pathways are common in cancer cells. In this study, we show that growth arrest (GA) treatments--serum and growth factor withdrawal and growth inhibitory IL-6 family cytokines (Interleukin-6 and Oncostatin M (OSM))--increase STAT3 phosphorylation (pSTAT3), increase CCAAT enhancer binding protein delta (C/EBPdelta) gene expression and induce GA of primary, finite-lifespan human mammary epithelial cells (HMECs), and immortalized breast cell lines (MCF-10A and MCF-12A). In contrast, serum and growth factor withdrawal from human breast cancer cell lines (MCF-7, SK-BR-3, T-47D, and MDA-MB-231) for up to 48 h induced a relatively modest increase in pSTAT3 levels and C/EBPdelta gene expression and resulted in varying levels of GA. In most breast cancer cell lines, IL-6 family cytokine treatment increased pSTAT3 levels and C/EBPdelta gene expression, however, growth inhibition was cell line dependent. In addition to "loss of function" alterations in growth inhibitory pathways, breast cancer cell lines also exhibit "gain of function" alterations in growth signaling pathways. The Akt growth/ survival pathway is constitutively activated in T-47D and MCF-7 breast cancer cells. The Akt inhibitor LY 294,002 significantly enhanced T-47D growth inhibition by serum and growth factor withdrawal or IL-6 family cytokine treatment. Finally, we show that activation of the pSTAT3/C/EBPdelta growth control pathway is independent of estrogen receptor status. These results demonstrate that "loss of function" alterations in the pSTAT3/C/EBPdelta growth inhibitory signal transduction pathway are relatively common in human breast cancer cell lines. Defective activation of the pSTAT3/ C/EBPdelta growth inhibitory signal transduction pathway, in conjunction with constitutive activation of the Akt growth stimulatory pathway, may play a synergistic role in the etiology or progression of breast cancer.     

ATM-heterozygous germline mutations contribute to breast cancer-susceptibility

Approximately 0.5%-1% of the general population has been estimated to be heterozygous for a germline mutation in the ATM gene. Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T) (MIM 208900). The finding that ATM-heterozygotes have an increased relative risk for breast cancer was supported by some studies but not confirmed by others. In view of this discrepancy, we examined the frequency of ATM germline mutations in a selected group of Dutch patients with breast cancer. We have analyzed ATM germline mutations in normal blood lymphocytes, using the protein-truncation test followed by genomic-sequence analysis. A high percentage of ATM germline mutations was demonstrated among patients with sporadic breast cancer. The 82 patients included in this study had developed breast cancer at age <45 and had survived >/=5 years (mean 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed. Among these patients we identified seven (8.5%) ATM germline mutations, of which five are distinct. One splice-site mutation (IVS10-6T-->G) was detected three times in our series. Four heterozygous carriers were patients with bilateral breast cancer. Our results indicate that the mutations identified in this study are "A-T disease-causing" mutations that might be associated with an increased risk of breast cancer in heterozygotes. We conclude that ATM heterozygotes have an approximately ninefold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival. The specific characteristics of our population of patients may explain why such a high frequency was not found in other series.     

Motor training programs of arm and hand in patients with MS according to different levels of the ICF: a systematic review

Background

Breast cancer survivors, particularly those treated with chemotherapy, are at significantly increased risk for long-term cognitive and neurobiologic impairments. These deficits tend to involve skills that are subserved by distributed brain networks. Additionally, neuroimaging studies have shown a diffuse pattern of brain structure changes in chemotherapy-treated breast cancer survivors that might impact large-scale brain networks.

Methods

We therefore applied graph theoretical analysis to compare the gray matter structural networks of female breast cancer survivors with a history of chemotherapy treatment and healthy age and education matched female controls.

Results

Results revealed reduced clustering coefficient and small-world index in the brain network of the breast cancer patients across a range of network densities. In addition, the network of the breast cancer group had less highly interactive nodes and reduced degree/centrality in the frontotemporal regions compared to controls, which may help explain the common impairments of memory and executive functioning among these patients.

Conclusions

These results suggest that breast cancer and chemotherapy may decrease regional connectivity as well as global network organization and integration, reducing efficiency of the network. To our knowledge, this is the first report of altered large-scale brain networks associated with breast cancer and chemotherapy.