Breast Cancer Latest Developments
The field of breast cancer research is a rapidly-moving one especially as this is a very well-funded area of cancer research. To help you find-out the latest news and discovery, the following articles are presented. To learn more, simply click of the article's title:
Breast Cancer Articles
MicroRNAs and their target gene networks in breast cancer
MicroRNAs (miRNAs) are a major class of small endogenous RNA molecules that post-transcriptionally inhibit gene expression. Many miRNAs have been implicated in several human cancers, including breast cancer. Here we describe the association between altered miRNA signatures and breast cancer tumorigenesis and metastasis. The loss of several tumor suppressor miRNAs (miR-206, miR-17-5p, miR-125a, miR-125b, miR-200, let-7, miR-34 and miR-31) and the overexpression of certain oncogenic miRNAs (miR-21, miR-155, miR-10b, miR-373 and miR-520c) have been observed in many breast cancers. The gene networks orchestrated by these miRNAs are still largely unknown, although key targets have been identified that may contribute to the disease phenotype. Here we report how the observed perturbations in miRNA expression profiles may lead to disruption of key pathways involved in breast cancer.
Are estrogen receptor positive breast cancers in BRCA1 mutation carriers sporadic?
There is a strong association between BRCA1 mutation carrier status and estrogen receptor negative breast cancer. This has led to the idea that estrogen receptor positive breast cancers in BRCA1 mutation carriers may be incidental or sporadic in nature and not as a direct result of BRCA1 dysfunction. A recent paper in Breast Cancer Research challenges this view.
Potential prognostic value of heat shock protein 90 in the presence of phosphatidylinositol-3-kinase overexpression or loss of PTEN, in invasive breast cancers
IntroductionEvaluating the expression of signaling molecule proteins from the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3-kinase (PI3K) pathway in invasive breast cancers may identify prognostic marker(s) associated with early relapse. Methods: Immunohistochemical analyses of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), PI3K-p110alpha, phospho-AKT, phospho-p70S6 kinase, phospho-S6 ribosomal protein, phospho-RAF, phospho-p44/42 MAPK, and heat shock protein 90 (HSP90) were performed on tumor samples from 212 patients with invasive breast cancer. Statistically significant relationships between protein expression, clinicopathologic factors, and relapse-free survival (RFS) were analyzed. Results: Expression of HSP90 was associated with 5-year RFS, as well as T stage, N stage, histologic grade, estrogen receptor (ER) expression, human epidermal growth factor receptor 2 (HER2) expression, and the Ki-67 proliferation index. On multivariate analysis, co-expression of HSP90 and PI3K-p110alpha or expression of HSP90 along with PTEN loss demonstrated significantly worse RFS. In subgroup analyses, both exhibited strong prognostic significance in HER2 positive cases, but not in HER2 negative cases. Conclusions: The co-expression of HSP90 with PI3K-p110alpha or expression of HSP90 along with PTEN loss have potential as molecular prognostic markers to predict early relapse in patients with invasive breast cancers.
Genetic variation in the estrogen metabolic pathway and mammographic density as an intermediate phenotype of breast cancer
IntroductionSeveral studies have examined the effect of genetic variants in genes involved in the estrogen metabolic pathway on mammographic density, but the number of loci studied and the sample sizes evaluated have been small and pathways have not been evaluated comprehensively. In this study, we evaluate the association between mammographic density and genetic variants of the estrogen metabolic pathway. Methods: A total of 239 single nucleotide polymorphisms (SNPs) in 34 estrogen metabolic genes were studied in 1731 Swedish women who participated in a breast cancer case-control study, of which 891 were cases and 840 were controls. Film mammograms of the medio-lateral oblique view were digitalized and the software Cumulus was used for computer-assisted semi-automated thresholding of mammographic density. Generalized linear models controlling for possible confounders were used to evaluate the effects of SNPs on mammographic density. Results found to be nominally significant were examined in two independent populations. The admixture maximum likelihood (AML) - based global test was performed to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion and estrogen removal. Results: Genetic variants of genes involved in estrogen metabolism exhibited no appreciable effect on mammographic density. None of the nominally significant findings were validated. In addition, global analyses on the overall estrogen metabolic pathway and its sub-pathways did not yield statistically significant results. Conclusions: Overall, there is no conclusive evidence that genetic variants in genes involved in the estrogen metabolic pathway are associated with mammographic density in postmenopausal women.
The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer
IntroductionHJURP (Holliday Junction Recognition Protein) is a newly discovered gene reported to function at centromeres and to interact with centromere protein A (CENP-A). However its role in tumor development remains largely unknown. The goal of this study was to investigate the clinical significance of HJURP in breast cancer and its correlation with radiotherapeutic outcome. Methods: We measured HJURP expression level in human breast cancer cell lines and primary breast cancers by Western blot and/or by Affymetrix Microarray; and determined its associations with clinical variables using standard statistical methods. Validation was performed with the use of published microarray data. We assessed cell growth and apoptosis of breast cancer cells after radiation using high-content image analysis. Results: HJURP was expressed at higher level in breast cancer than in normal breast tissue. HJURP mRNA levels were significantly associated with estrogen receptor (ER), progesterone receptor (PR), Scarff-Bloom-Richardson (SBR) grade, age and Ki67 proliferation indices, but not with pathologic stage, ERBB2, tumor size, or lymph node status. Higher HJURP mRNA levels significantly decreased disease-free and overall survival. HJURP mRNA levels predicted the prognosis better than Ki67 proliferation indices. In a multivariate Cox proportional-hazard regression, including clinical variables as covariates, HJURP mRNA levels remained an independent prognostic factor for disease-free and overall survival. In addition HJURP mRNA levels were an independent prognostic factor over molecular subtypes (normal like, luminal, Erbb2 and basal). Poor clinical outcomes among patients with high HJURP expression were validated in five additional breast cancer cohorts. Furthermore, the patients with high HJURP levels were much more sensitive to radiotherapy. In vitro studies in breast cancer cell lines showed that cells with high HJURP levels were more sensitive to radiation treatment and had a higher rate of apoptosis than those with low levels. Knock down of HJURP in human breast cancer cells using shRNA reduced the sensitivity to radiation treatment. HJURP mRNA levels were significantly correlated with CENP-A mRNA levels. Conclusions: HJURP mRNA level is a prognostic factor for disease-free and overall survival in patients with breast cancer and is a predictive biomarker for sensitivity to radiotherapy.
Prediction of breast cancer sensitivity to neoadjuvant chemotherapy based on status of DNA damage repair proteins
IntroductionVarious agents used in breast cancer chemotherapy provoke DNA double-strand breaks (DSBs). DSB repair competence determines the sensitivity of cells to these agents whereby aberrations in the repair machinery leads to apoptosis. Proteins required for this pathway can be detected as nuclear foci at sites of DNA damage when the pathway is intact. Here we investigate whether focus formation of repair proteins can predict chemosensitivity of breast cancer. Methods: Core needle biopsy specimens were obtained from sixty cases of primary breast cancer before and 18-24 hours after the first cycle of neoadjuvant epirubicin plus cyclophosphamide (EC) treatment. Nuclear focus formation of DNA damage repair proteins was immunohistochemically analyzed and compared with tumor response to chemotherapy. Results: EC treatment induced nuclear foci of H2AX, conjugated ubiquitin, and Rad51 in a substantial amount of cases. In contrast, BRCA1 foci were observed before treatment in the majority of the cases and only decreased after EC in thirteen cases. The presence of BRCA1-, H2AX-, or Rad51-foci before treatment or the presence of Rad51-foci after treatment was inversely correlated with tumor response to chemotherapy. DNA damage response (DDR) competence was further evaluated by considering all four repair indicators together. A high DDR score significantly correlated with low tumor response to EC and EC + docetaxel whereas other clinicopathological factors analyzed did not. Conclusions: High performing DDR focus formation resulted in tumor resistance to DNA damage-inducing chemotherapy. Our results suggested an importance of evaluation of DDR competence to predict breast cancer chemosensitivity, and merits further studying into its usefulness in exclusion of non-responder patients.
Effects of lovastatin on breast cancer cells: a proteo-metabonomic study
IntroductionStatins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation and reduction of signals driving cell proliferation and survival responses. Methods: In this study we evaluated the effects of lovastatin acid and lactone on breast cancer MDAMB231 and MDAMB468 cells using a combination of proteomic and metabonomic profiling techniques. Results: Lovastatin inhibited proliferation of breast cancer cell lines. MDAMB231 cells were more sensitive to its effects, and in most cases lovastatin acid showed more potency towards the manipulation of protein expression than lovastatin lactone. Increased expression of Rho inhibitor GDI-2 stabilized the non-active Ras homolog gene family member A (RhoA) leading to a decreased expression of its active, membrane-bound form. Its downstream targets cofilin, CDC42 and G3BP1 are members of the GTPase family affected by lovastatin. Our data indicated that lovastatin modulated the E2F1-pathway through the regulation of expression of prohibitin and retinoblastoma (Rb). This subsequently leads to changes of E2F-downstream targets minichromosome maintenance protein 7 (MCM7) and MutS homolog 2 (MSH2). Lovastatin also regulated the AKT-signaling pathway. Increased phosphatase and tensin homolog (PTEN) and decreased DJ-1 expression lead to a down-regulation of the active pAkt. Lovastatin's involvement in the AKT-signaling pathway was confirmed by an upregulation of its downstream target, tumor progressor NDRG1. Metabolic consequences to lovastatin exposure included suppression of glycolytic and Krebs cycle activity, and lipid biosynthesis. Conclusions: The combination of proteomics and metabonomics enabled us to identify several key targets essential to the antitumor activity of lovastatin. Our results imply that lovastatin has the potential to reduce the growth of breast cancer cells.
Correction: PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer
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Prescriptions for selective cyclooxygenase-2 inhibitors, non-selective non-steroidal anti-inflammatory drugs, and risk of breast cancer in a population-based case-control study
IntroductionNon-steroidal anti-inflammatory drugs (NSAIDs) prevent the growth of mammary tumours in animal models. Two population-based case-control studies suggest a reduced risk of breast cancer associated with selective cyclooxygenase-2 (sCox-2) inhibitor use, but data regarding the association between breast cancer occurrence and use of non-selective NSAIDs are conflicting. Methods: We conducted a population-based case-control study using Danish healthcare databases to examine if use of NSAIDs, including sCox-2 inhibitors, was associated with a reduced risk of breast cancer. We included 8,195 incident breast cancer cases diagnosed 1991 through 2006 and 81,950 population controls. Results: Overall, we found no reduced breast cancer risk in ever users (>2 prescriptions) of sCox-2 inhibitors [odds ratio (OR)=1.08, 95% confidence interval (95%CI)=0.99, 1.18), aspirin (OR=0.98, 95%CI=0.90-1.07), or non-selective NSAIDs OR=1.04, (95%CI=0.98, 1.10)]. Recent use (>2 prescriptions within 2 years of index date) of sCox-2 inhibitors, aspirin, or non-selective NSAIDs was likewise not associated with breast cancer risk [ORs=1.06 (95%CI=0.96, 1.18), 0.96 (95%CI=0.87, 1.06) and 0.99 (95%CI=0.85, 1.16), respectively]. Risk estimates by duration (<10, 10-15, 15+ years) or intensity (low/medium/high) of NSAID use were also close to unity. Regardless of intensity, shorter or long-term NSAID use was not significantly associated with breast cancer risk. Conclusions: Overall, we found no compelling evidence of a reduced risk of breast cancer associated with use of sCox-2 inhibitors, aspirin, or non-selective NSAIDs.
Risk of breast cancer among daughters of mothers with diabetes: a population-based cohort study
IntroductionDiabetes during pregnancy is related to enhanced fetal growth, which has been associated with increased breast cancer risk. Whether daughters of mothers with a diagnosis of diabetes have an increased risk of breast cancer is not known. Methods: We performed a retrospective cohort study of daughters of mothers with diabetes by linkage of the Swedish Multigeneration, Cause-of-Death and Patient Register between 1952 and 2005. Breast cancer cases were ascertained by linkage with the Swedish Cancer Register between 1958 and 2005. Standardized incidence ratios (SIRs) of breast cancer were calculated assuming a Poisson distribution for the observed cases. Results: We identified 291,360 daughters of mothers with a diagnosis of diabetes before or after birth between 1952 and 2005. Among the daughters, 7956 cases of breast cancer were diagnosed between 1964 and 2005. The total time of follow-up was 12,173,821 person years. The expected number of breast cancer cases was 9204, resulting in an SIR of 0.86 (95 % CI, 0.85 to 0.88). The decrease in risk associated with maternal diabetes was stronger for premenopausal (<55 years of age) than postmenopausal ([greater than or equal to]55 years of age) breast cancer (SIR 0.83 and 0.91, respectively). Among daughters of mothers' with diabetes, a history of breast cancer in the mother increased the risk of breast cancer in the daughter (SIR 1.43, 1.32 to 1.54). Conclusions: Daughters of mothers with a lifetime history of diabetes were at a decreased risk of breast cancer. The strongest negative association was found among premenopausal breast cancer.