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
The role and function of cadherins in the mammary gland
Cadherins are transmembrane receptors that function through calcium-dependent homophilic and heterophilic interactions that provide cell-cell contact and communication in many different organ systems. In the mammary gland only a few of the cadherins that make up this large superfamily of proteins have been characterized. Frequently in metastatic breast cancer, the genes for cadherins are epigenetically silenced, mutated, or regulated differently. During epithelial mesenchymal transition, cadherins that are expressed normally in the epithelial cells are down regulated, while cadherins expressed in the mesenchyme are up regulated. This process is known as cadherin switching, and its regulation can sometime facilitates the increase motility, invasiveness and proliferation that occurs in metastatic cancer cells. However, depending on the context, cell motility, invasiveness, proliferation and expression of mesenchymal markers can be independently modulated from cadherin expression leading to partial epithelial mesenchymal transitions and even mesenchymal-epithelial transitions. This review will summarize the current understanding of cadherins found in the mammary gland and what is known about their mechanism of regulation in the mammary gland during normal physiological conditions and in breast cancer.
Initiating breast cancer by PIK3CA mutation
PIK3CA mutations confer constitutive activation of PI3K, which initiates intracellular kinase signaling cascades that promote cell proliferation and survival. Recent studies by Meyer et al. and Liu et al. demonstrate that expression of the H1047R exon 20 mutant of PIK3CA in luminal mammary epithelial cells induces tumorigenesis, implying that PIK3CA mutations are an early event in breast cancer. PIK3CA-H1047R-initiated tumors exhibit variable dependence on the oncogene, and variable sensitivity to PI3K inhibition. Amplification of the oncogenes MYC and MET was observed in tumors which recurred following silencing of PIK3CA-H1047R, suggesting that these pathways represent mechanisms of escape from PI3K inhibition.
Breast cancer risk prediction and individualised screening based on common genetic variation and breast density measurement
IntroductionOver the last decade several breast cancer risk alleles have been identified which has led to an increased interest in individualised risk prediction for clinical purposes. Methods: We investigate the performance of an up-to-date 18 breast cancer risk single-nucleotide polymorphisms (SNPs), together with mammographic percentage density (PD), body mass index (BMI) and clinical risk factors in predicting absolute risk of breast cancer, empirically, in a well characterised Swedish case-control study of postmenopausal women. We examined the efficiency of various prediction models at a population level for individualized screening by extending a recently proposed analytical approach for estimating number of cases captured. Results: The performance of a risk prediction model based on an initial set of seven breast cancer risk SNPs is improved by additionally including eleven more recently established breast cancer risk SNPs (P = 4.69 x 10-4). Adding mammographic PD, BMI and all 18 SNPs to a Swedish Gail model improved the discriminatory accuracy (the AUC statistic) from 55% to 62%. The net reclassification improvement was used to assess improvement in classification of women into low, intermediate, and high categories of 5-year risk (P = 8.93 x 10-9). For scenarios we considered, we estimated that an individualized screening strategy based on risk models incorporating clinical risk factors, mammographic density and SNPs, captures 10% more cases than a screening strategy using the same resources, based on age alone. Estimates of numbers of cases captured by screening stratified by age provide insight into how individualised screening programs might appear in practice. Conclusions: Taken together, genetic risk factors and mammographic density offer moderate improvements to clinical risk factor models for predicting breast cancer.
Germline DNA copy number variation in familial and early-onset breast cancer
IntroductionGenetic factors for cancer predisposition remain elusive in the majority of patients with familial or clinical history suggestive of hereditary breast cancer. Germline DNA copy-number variation (CNV) has recently been implicated in predisposition to cancer such as neuroblastoma, prostate and colorectal. We evaluated the role of germline CNVs in breast cancer susceptibility, in particular those with low population frequencies (rare CNVs), which are more likely to impact disease. Methods: Using whole genome array-CGH, we screened a cohort of women fulfilling criteria for hereditary breast cancer, who did not carry BRCA1/BRCA2 mutations. Results: The median number of total and rare CNVs per genome were not different between controls and patients. However, a total of 26 rare germline CNVs were identified in 68 cancer patients, a proportion that was significantly different (P=0.0311) from the control group (23 rare CNVs in 100 individuals). Several of the genes affected by CNV variation in patients and controls had already been implicated in cancer. Conclusions: This is the first study to explore the contribution of germline CNVs to BRCA1/2 negative familial and early-onset breast cancer. The data suggest that rare CNVs may contribute to cancer predisposition in this small cohort of patients, and this trend needs to be confirmed in larger samples.
Contribution of CXCL12 secretion to invasion of breast cancer cells
IntroductionNeu (HER2/ErbB2) is over-expressed in 25-30% of human breast cancer, correlating with a poor prognosis. Previous studies using the Neu transgenic mouse model (MMTV-Neu) demonstrated that the Neu-YB line had increased production of CXCL12 and increased metastasis, while the Neu-YD line had decreased metastasis. This study examines the role of increased production of CXCL12 in tumor cell invasion and malignancy. Methods: We studied invasion in the tumor microenvironment using multiphoton intravital imaging, in vivo invasion, and intravasation assays. CXCL12 signaling was altered by using the CXCR4 inhibitor AMD3100 or increasing CXCL12 expression. The role of macrophage signaling in vivo was determined using a colony stimulating factor-1 (CSF-1) receptor blocking antibody. Results: The Neu-YD strain was reduced in invasion, intravasation, and metastasis compared to the Neu-YB and Neu-NDL strains. Remarkably, for the Neu-YB strain, in vivo invasion to epidermal growth factor was dependent on both CXCL12/CXCR4 and CSF1/CSF1R signaling. Neu-YB tumors had increased macrophage and microvessel density. Over-expression of CXCL12 in MTLn3 cells increased in vivo invasion, as well as microvessel and macrophage densities. Conclusions: Expression of CXCL12 by tumor cells results in increased macrophage and microvessel density and in vivo invasiveness.
Small interfering RNA library screen identified polo-like kinase-1 (PLK1) as a potential therapeutic target for breast cancer that uniquely eliminates tumour-initiating cells
IntroductionTriple negative breast cancers' (TNBCs) high rate of relapse is thought to be due to the presence of tumor-initiating cells (TICs), molecularly defined as being CD44high/CD24-/low. TICs are resilient to chemotherapy and radiation. However, there is no currently accepted molecular target against TNBC and moreover TICs. Therefore, we sought the identification of kinase targets that inhibit TNBC growth and eliminate TICs. Methods: A genome-wide human kinase siRNA library (691 kinases) was screened against the TNBC cell line SUM149 for growth inhibition. Selected siRNAs were then tested on four different breast cancer cell lines to confirm the spectrum of activity. Their effect on CD44high subpopulation and sorted CD44high/CD24-/low cells of SUM149 was also studied. Further studies were focused on polo-like kinase 1 (PLK1), including its expression in breast cancer cell lines, effect on CD44high/CD24-/low TIC subpopulation, growth inhibition, mammosphere formation and apoptosis as well as the activity of the PLK1 inhibitor, BI 2536. Results: 85 kinases were identified in the screen. 28 of them were further silenced by siRNAs on MDA-MB-231 (TNBC), BT474-M1 (ER+/HER2+, a metastatic variant) and HR5 (ER+/HER2+, a trastuzumab-resistant model) cells and showed broad spectrum of growth inhibition. Importantly, 12/28 kinases also reduced CD44high subpopulation compared to control in SUM149. Further tests of these 12 kinases directly on sorted CD44high/CD24-/low TIC subpopulation of SUM149 cells confirmed their effect. Blocking PLK1 had the greatest growth inhibition on breast cancer cells and TICs by ~80-90% after 72 hours. PLK1 was universally expressed in breast cancer cell lines representing all of the breast cancer subtypes, and was positively correlated to CD44. The PLK1 inhibitor BI 2536 showed similar effects on growth, mammosphere formation and apoptosis as PLK1 siRNAs. Finally, while paclitaxel, doxorubicin and 5-fluorouracil enriched CD44high/CD24-/low population compared to control in SUM149, subsequent treatment with BI 2536 killed the emergent population suggesting it could potentially be used to prevent relapse. Conclusion: Inhibiting PLK1 with siRNA or BI 2536 blocked growth of TNBCs including the CD44high/CD24-/low TIC subpopulation and mammosphere formation. Thus, PLK1 could be a potential therapeutic target for the treatment of TNBC as well as other subtypes of breast cancer.
Use of glucocorticoids and risk of breast cancer: a Danish population-based case-control study
IntroductionGlucocorticoids are widely prescribed drugs. In the human body, glucocorticoid is the main stress hormone, and controls a variety of physiological and cellular processes, including metabolism and immune response. It belongs to the same steroid superfamily as estrogens, which are known to play a role in breast cancer. However, the effect of glucocorticoid use on the risk of breast cancer is not clear. Methods: We conducted a case-control study using population-based medical databases from Northern Denmark (1.8 million inhabitants) to investigate the association between glucocorticoid prescriptions and breast cancer risk. The study included 9,488 incident breast cancer cases diagnosed between 1994 and 2008 and 94,876 population controls. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) associating glucocorticoid use with breast cancer occurrence, controlling for prescriptions of postmenopausal hormone replacement therapy, anti-diabetics, immunosuppressive drugs, and hospital diagnosis of obesity, diabetes, chronic pulmonary diseases and autoimmune diseases. Results: We found no effect on breast cancer risk in ever users (>2 prescriptions) of any glucocorticoids (adjusted OR (aOR)=1.0; 95% CI: 0.96, 1.1), systemic glucocorticoids (aOR=1.0; 95% CI: 0.96, 1.1), or inhaled glucocorticoids (aOR=1.0; 95% CI: 0.95, 1.1), each compared to never users of any glucocorticoids. Associations for recent use (preceding 2 years) and former use (more than 2 years earlier) were near null in all dose categories (low, medium and high number of prescriptions). Intensity of systemic glucocorticoid use (cumulative prednisolone equivalent doses), regardless of duration (<1, 1-5, 5+ years), was also not associated with breast cancer risk. Conclusions: Overall, our study provides no evidence that glucocorticoid use affects the risk of breast cancer.
Do we need biomarkers to predict the benefit of adding adjuvant taxanes for treatment of breast cancer?
The current understanding of the molecular biology of breast cancer presents an extremely complex portrait of the disease. Based on this knowledge, considerable efforts are being made to identify biomarkers that will predict the response to a specific treatment while minimizing the risk of unnecessary side effects. In breast cancer, the Ki67 index has been associated with poor prognosis and might play a relevant role in predicting benefit from adjuvant docetaxel, as observed in the article accompanying this editorial. Taxanes are one of the most active cytotoxic agents for breast cancer. However, the role of taxane-based chemotherapy as adjuvant treatment of early breast cancer remains controversial in some subsets of patients. For this reason, the Ki67 index might help to better define the group of patients who could have the optimal benefit.
Phospho-ibuprofen (MDC-917) suppresses breast cancer growth: an effect controlled by the thioredoxin system
IntroductionWe have recently synthesized phospho-ibuprofen (MDC-917; P-I), a safer derivative of ibuprofen, which has shown anticancer activity. We investigated its efficacy and mechanism of action in the treatment of breast cancer in preclinical models. Methods: We evaluated the anti-breast cancer efficacy of P-I alone or incorporated into liposomes (Lipo-P-I) in human ER (+) (MCF-7) and triple-negative (ER(-), PgR(-) and HER2(-); MDA-MB231) breast cancer cell lines, as they represent the most frequent (ER(+)) and the most difficult to treat (triple-negative) subtypes of breast cancer , and their xenografts in nude mice. We assessed the effect of P-I on a) the levels of reactive oxygen nitrogen species in response to P-I using molecular probes; b) the thioredoxin system (expression and redox status of thioredoxin-1 (Trx-1) and thioredoxin reductase activity); c) cyclooxygenase 2 (COX-2), nuclear factor KB (NF-KB) and mitogen-activated protein kinase (MAPK) cell signaling; and d) the growth of xenografts with stably knocked-down Trx-1. Results: Compared to controls, a) P-I 400 mg/kg/day inhibited the growth of MDA-MB231 xenografts 266%; and b) P-I 300 mg/kg/day inhibited the growth of MCF-7 xenografts 51% and Lipo-P-I at the same dose 181%. In both cell lines, P-I induced oxidative stress and suppressed the Trx system (oxidized Trx-1 and decreased its expression; inhibited thioredoxin reductase activity). These changes triggered downstream redox signaling: the activity of NF-KB was suppressed and the Trx-1-ASK1 complex was dissociated, activating the p38 and JNK MAPK cascades. Trx-1 knockdown abrogated P-I's anticancer effect in vitro and in vivo. Conclusions: P-I is safe and effective against breast cancer. Liposomal formulation enhances its efficacy; its effect is heavily dependent on the induction of oxidative stress and the suppression of the thioredoxin system. P-I merits further evaluation as an agent for the treatment of breast cancer.
Validation of the Gail model for predicting individual breast cancer risk in a prospective nationwide study of 28,104 Singapore women
IntroductionThe Gail model (GM) is a risk-assessment model used in individual estimation of the absolute risk of invasive breast cancer, and has been applied to both clinical counselling and breast cancer prevention studies. Although the GM has been validated in several Western studies, its applicability outside North America and Europe remains uncertain. The Singapore Breast Cancer Screening Project (SBCSP) is a nation-wide prospective trial of screening mammography conducted between Oct 1994 and Feb 1997, and is the only such trial conducted outside North America and Europe to date. With the long-term outcomes from this study, we sought to evaluate the performance of GM in prediction of individual breast cancer risk in an Asian-developed country. Methods: The study population comprised of 28,104 women aged 50 to 64 years who participated in the SBSCP and did not have breast cancer detected during screening. The national cancer registry was used to identify incident cases of breast cancer. To evaluate the performance of the GM, we compared the expected number of invasive breast cancer cases predicted by the model to the actual number of cases observed within 5-year and 10-year follow-up. Pearson's Chi-square test was used to test the goodness of fit between the expected and observed cases of invasive breast cancers. Results: The ratio of expected to observed number of invasive breast cancer cases within 5-year from screening was 2.51 (95% confidence interval 2.14 - 2.96). The GM over-estimated breast cancer risk across all age groups, with the discrepancy highest among older women aged 60 - 64 years (E/O = 3.53, 95% CI = 2.57 - 4.85). The model also over-estimated risk for the upper 80% of women with highest predicted risk. The overall E/O ratio for the 10-year predicted breast cancer risk was 1.85 (1.68 - 2.04). Conclusions: The GM over-predicts the risk of invasive breast cancer in an Asian developed-country setting as demonstrated in a large prospective trial, with the largest difference seen in older women aged between 60 and 64 years old. The reason for the discrepancy is likely to be multifactorial, including a true reduction of breast cancer, as well as lower mammographic screening prevalence locally.