http://breast-cancer-research.com/ The latest research articles published by Breast Cancer Research 2013-05-16T00:00:00Z IntroductionOverdiagnosis in breast cancer screening is a controversial topic. One difficulty in estimation of overdiagnosis is the separation of overdiagnosis from lead time that is the advance in the time of diagnosis of cancers, which confers an artificial increase in incidence when a screening programme is introduced. Methods: We postulated a female population aged 50-79 with a similar age structure and age-specific breast cancer incidence as in England and Wales before the screening programme. We then imposed a two-yearly screening programme; screening women aged 50-69, to run for twenty years, with exponentially distributed lead time with an average of 40 months in screen-detected cancers. We imposed no effect of the screening on incidence other than lead time. Results: Comparison of age- and time-specific incidence between the screened and unscreened populations showed a major effect of lead time, which could only be adjusted for by follow-up for more than two decades and including ten years after the last screen. From lead time alone, twenty-year observation at ages 50-69 would confer an observed excess incidence of 37%. The excess would only fall below 10% with 25 years or more follow-up. For the excess to be nullified, we would require 30 year follow-up including observation up to 10 years above the upper age limit for screening. Conclusions: Studies using shorter observation periods will overestimate overdiagnosis by inclusion of cancers diagnosed early due to lead time among the nominally overdiagnosed tumours. http://breast-cancer-research.com/content/15/3/R41 Stephen Duffy Dharmishta Parmar Breast Cancer Research 2013, null:R41 2013-05-16T00:00:00Z doi:10.1186/bcr3427 /content/figures/bcr3427-toc.gif Breast Cancer Research 1465-5411 ${item.volume} R41 2013-05-16T00:00:00Z PDF Breast cancer is a complex and heterogeneous disease that affects about one out of every eight women. In the last decade, several advancements have been made that have increased our understanding of breast cancer and have allowed us to more accurately diagnose and treat this disease in a more targeted manner. For example, gene expression profiling enabled the classification of breast cancers into four main subtypes - basal-like, HER2+ (human epidermal growth factor receptor 2-positive), luminal A and luminal B - and this classification is used to direct the use of targeted therapies such as tamoxifen or trastuzumab. The luminal subtypes are generally characterized as being estrogen receptor-positive and targetable with anti-hormone therapies. However, whereas luminal A cancers have a good prognosis, luminal B cancers are associated with early relapse following endocrine therapy and a prognosis that is similar to that of the aggressive basal subtype. It is thus imperative that luminal B cancers be better characterized so that therapeutic targets and biomarkers for this disease type can be realized. In the previous issue of Breast Cancer Research, Katchman and colleagues address this need by demonstrating that quiescin sulfydryl oxidase 1 (QSOX1), a secreted enzyme involved in post-translational modifications, is associated with poor prognosis in patients with luminal B breast cancer. The authors further determined that this protein promotes breast cancer proliferation and invasion. Collectively, these studies suggest that QSOX1 is a predictive biomarker for luminal cancers and that it may be a useful target for elusive luminal B disease. http://breast-cancer-research.com/content/15/3/104 Padmalaya Das Gabrielle Siegers Lynne-Marie Postovit Breast Cancer Research 2013, null:104 2013-05-15T00:00:00Z doi:10.1186/bcr3417 /content/figures/bcr3417-toc.gif Breast Cancer Research 1465-5411 ${item.volume} 104 2013-05-15T00:00:00Z XML IntroductionPercent mammographic density (PMD) adjusted for age and BMI is one of the strongest risk factors for breast cancer and is known to be approximately 60 percent heritable. Here we report a finding of an association between genetic ancestry and adjusted PMD. Methods: We selected self-identified Caucasian women in the California Pacific Medical Center Research Institute Cohort whose screening mammograms placed them in the top or bottom quintiles of age- and body mass index-adjusted PMD. Our final data set included 474 women with the highest adjusted PMD and 469 with the lowest genotyped on the Illumina 1M platform. Principal component analysis (PCA) and identity-by-descent (IBD) analyses allowed us to infer the women's genetic ancestry and correlate it with adjusted PMD. Results: Women of Ashkenazi Jewish ancestry, as defined by the first principal component (PC1) of PCA and identity-by-descent analyses, represented approximately 15 percent of the sample. Ashkenazi Jewish ancestry, defined by PC1, was associated with higher adjusted PMD (p = 0.004). Using multivariate regression to adjust for epidemiologic factors associated with PMD, including age at parity and use of postmenopausal hormone therapy, did not attenuate the association. Conclusion: Women of Ashkenazi Jewish ancestry based on genetic analysis are more likely to have high age- and BMI-adjusted PMD. Ashkenazi Jews may have a unique set of genetic variants or environmental risk factors that increase mammographic density. http://breast-cancer-research.com/content/15/3/R40 Jennifer Caswell Karla Kerlikowske John Shepherd Steven Cummings Donglei Hu Scott Huntsman Elad Ziv Breast Cancer Research 2013, null:R40 2013-05-13T00:00:00Z doi:10.1186/bcr3424 /content/figures/bcr3424-toc.gif Breast Cancer Research 1465-5411 ${item.volume} R40 2013-05-13T00:00:00Z PDF IntroductionDysregulation of the insulin-like growth factor-1 receptor (IGF-1R)/ PI3K/Akt pathway was shown to correlate with breast cancer disease progression. Cancer stem cells (CSCs) are a subpopulation within cancer cells which participate in tumor initiation, radio/chemoresistance and metastasis. In breast cancer, breast CSCs (BCSCs) were identified as CD24-CD44+ cells or cells with high intracellular aldehyde dehydrogenase activity (ALDH+). Elucidation of the role of IGF-1R in breast cancer stem cells (BCSCs) is crucial to the design of breast cancer therapies targeting BCSCs. Methods: IGF-1R expression in BCSCs and non-CSCs sorted from xenografts of human primary breast cancers was examined by FACS, western blot analysis and immunoprecipitation (IP). The role of IGF-1R in BCSCs was assessed by IGF-1R blockade with chemical inhibitor and gene silencing. The involvement of PI3K/Akt/mTOR as downstream pathway was studied by their phosphorylation status upon IGF-1R inhibition and the effects of chemical inhibitors of these signaling molecules on BCSCs. We also studied 16 clinical specimens of breast cancer for the expression of phosphor-Akt in the BCSCs by FACS. Results: Expression of phosphorylated IGF-1R was greater in BCSCs than in non-BCSCs from xenografts of human breast cancer which were supported by western blot and IP experiments. The sorted IGF-1R expressing cells displayed features of cancer stem/progenitors such as mammosphere formation in vitro and tumorigenicity in vivo, both of which were suppressed by knockdown of IGF-1R. A specific inhibitor of the IGF-1R, PPP, suppressed the phospho-AktSer473 and preferentially decreased ALDH+ BCSC populations of human breast cancer cells. Furthermore, PPP inhibited the capacity of CD24-CD44+ BCSCs to undergo epithelial-mesenchymal transition process with downregulation of mesenchymal markers. Inhibitors of signal molecules downstream of IGR-1R including PI3K/Akt/mTOR also reduced the ALDH + population of breast cancer cells. Furthermore, the mTOR inhibitor, rapamycin, suppressed BCSCs in vitro and in vivo. Conclusions: Our data support the notion that IGF-1R is a marker of stemness, and IGF-1R and its downstream PI3K/Akt/mTOR pathway are attractive targets for therapy directed against breast cancer stem/progenitors. http://breast-cancer-research.com/content/15/3/R39 Wen-Wei Chang Ruey-Jen Lin John Yu Wen-Ying Chang Chiung-Hui Fu Alan Chuan-Ying Lai Jyh-Cherng Yu Alice L Yu Breast Cancer Research 2013, null:R39 2013-05-12T00:00:00Z doi:10.1186/bcr3423 /content/figures/bcr3423-toc.gif Breast Cancer Research 1465-5411 ${item.volume} R39 2013-05-12T00:00:00Z PDF IntroductionOf the nearly 1.4 million new cases of breast cancer diagnosed each year, a large proportion is characterized as hormone receptor negative, lacking estrogen receptors (ER) and/or progesterone receptors (PR). Patients with receptor-negative tumors do not respond to current steroid hormone based therapies and generally have significantly higher risk of recurrence and mortality compared to patients with tumors that are ER- and/or PR-positive. Previous in vitro studies had shown that the progesterone metabolites, 5alpha-dihydroprogesterone (5alphaP) and 3alpha-dihydroprogesterone (3alphaHP), respectively, exhibit pro-cancer and anti-cancer effects on receptor-negative human breast cell lines. Here in vivo studies were conducted to investigate the ability of 5alphaP and 3alphaHP to control initiation, growth and regression of ER/PR-negative human breast cell tumors. Methods: ER/PR-negative human breast cells (MDA-MB-231) were implanted into mammary fat pads of immunosuppressed mice and the effects of 5alphaP and 3alphaHP treatments on tumor initiation, growth, suppression/regression and histopathology were assessed in five separate experiments. Specific radioimmunoassays and gas chromatography-mass spectrometry were used to measure 5alphaP, 3alphaHP and progesterone in mouse serum and tumors. Results: Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5alphaP and inhibited by 3HP. When both hormones were applied simultaneously, the stimulatory effects of 5P were abrogated by the inhibitory effects of 3alphaHP and vice versa. Treatment with 3alphaHP subsequent to 5alphaP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. The levels of 5alphaP in tumors, regardless of treatment, were about 10-fold higher than the levels of 3alphaHP and the 5alphaP:3alphaHP ratios were about 5-fold higher than in serum, indicating significant changes in endogenous synthesis of these hormones in tumorous breast tissues. Conclusions: The studies showed that estrogen/progesterone insensitive breast tumors are sensitive to, and controlled by, the progesterone metabolites 5alphaP and 3alphaHP. Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5alphaP and suppressed by 3alphaHP, the outcome depending upon the relative concentrations of these two hormones in the microenvironment in the breast regions. The findings show that the production of 5alphaP greatly exceeds that of 3alphaHP in ER/PR-negative tumors and that treatment with 3alphaHP can effectively block tumorigenesis and regress existing tumors. The results provide the first hormonal theory to explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis that a high 3alphaHP-to-5alphaP concentration ratio in the microenvironment may foster normalcy in non-cancerous breast regions. The findings suggest new diagnostics based on the relative levels of these hormones and new approaches to prevention and treatment of breast cancers based on regulating the levels and action mechanisms of anti- and pro-cancer progesterone metabolites. http://breast-cancer-research.com/content/15/3/R38 John Wiebe Guihua Zhang Ian Welch Heather-Anne Cadieux-Pitre Breast Cancer Research 2013, null:R38 2013-05-11T00:00:00Z doi:10.1186/bcr3422 /content/figures/bcr3422-toc.gif Breast Cancer Research 1465-5411 ${item.volume} R38 2013-05-11T00:00:00Z PDF IntroductionMolecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analysed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors. Methods: We performed quantitative reverse transcription PCR (qRT-PCR) for ER, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, HER2, CK5/6, CK17, EGFR, Ki67, AR, FOXA1 and GCDFP15 and we analysed clinical features. Results: MA tumors were all characterized by ER(-) AR(+) FOXA1(+) and AR-related genes positive mRNA profile. IHC staining on these tumors showed 93% ER(-), only 58% AR(+) and 90% FOXA1(+). 67% and 57% MA tumors were HER2(3+) and GCDFP15(+), respectively. Almost all MA tumors (94%) had the IHC signature "HER2(3+) or GCDFP15(+)" but none of 13 control basal-like (BL) tumors did. Clinically, MA tumors were rather aggressive, with poor prognostic factors. Conclusion: MA tumors could be better defined by their qRT-PCR-AR profile than by AR IHC. In addition, we found that "HER2 or GCDFP15" protein overexpression is a sensitive and specific tool to differentiate MA from BL in the context of ER negative tumors. A composite molecular and IHC signature could therefore help to identify MA tumors in the daily practice. http://breast-cancer-research.com/content/15/3/R37 Jacqueline Lehmann-Che Anne Sophie Hamy Raphael Porcher Marc Barritault Fatiha Bouhidel Hanadi Habuellelah Solenne Leman-Detours Anne de Roquancourt Laurence Cahen-Doidy Edwige Bourstyn Patricia de Cremoux Cedric de Bazelaire Marcela Albiter Sylvie Giacchetti Caroline Cuvier Anne Janin Marc Espie Hugues de The Philippe Bertheau Breast Cancer Research 2013, null:R37 2013-05-11T00:00:00Z doi:10.1186/bcr3421 New molecular apocrine breast tumour signature <p>A novel and simplified molecular and immunohistochemical signature has been described for molecular apocrine breast tumours which could help with easy identification in clinical practice.</p> /content/figures/bcr3421-toc.gif Breast Cancer Research 1465-5411 ${item.volume} R37 2013-05-11T00:00:00Z PDF The discovery of RNA interference has opened the door for the development of a new class of cancer therapeutics. Small inhibitory RNA oligos are being designed to specifically suppress expression of proteins that are traditionally considered nondruggable, and microRNAs are being evaluated to exert broad control of gene expression for inhibition of tumor growth. Since most naked molecules are not optimized for in vivo applications, the gene silencing agents need to be packaged into delivery vehicles in order to reach the target tissues as their destinations. Thus, the selection of the right delivery vehicles serves as a crucial step in the development of cancer therapeutics. The current review summarizes the status of gene silencing agents in breast cancer and recent development of candidate cancer drugs in clinical trials. Nanotechnology-based delivery vectors for the formulation and packaging of gene silencing agents are also described. http://breast-cancer-research.com/content/15/3/205 Haifa Shen Vivek Mittal Mauro Ferrari Jenny Chang Breast Cancer Research 2013, null:205 2013-05-08T00:00:00Z doi:10.1186/bcr3413 /content/figures/bcr3413-toc.gif Breast Cancer Research 1465-5411 ${item.volume} 205 2013-05-08T00:00:00Z XML The recent paper by Meier-Abt and colleagues on pregnancy protection of breast cancer development takes a different approach to the problem and focused on the effect of parity on the cell subpopulations of the mouse mammary gland. Their results demonstrate that parity decreases the cell number of the hormone receptor-positive luminal cells (that is, luminal Sca1+) but not the basal stem/progenitor cells (CD24lo/CD49hi). Additionally, microarray studies demonstrate that wnt4 expression from the luminal Sca1+ cells is markedly reduced as is the wnt signaling pathway in basal cells. One important implication from these results is that targeting the wnt signaling pathway might be a feasible prevention approach in humans. http://breast-cancer-research.com/content/15/3/103 Daniel Medina Breast Cancer Research 2013, null:103 2013-05-08T00:00:00Z doi:10.1186/bcr3414 /content/figures/bcr3414-toc.gif Breast Cancer Research 1465-5411 ${item.volume} 103 2013-05-08T00:00:00Z XML IntroductionEarly pregnancy has a strong protective effect against breast cancer in humans and rodents, but the underlying mechanism is unknown. Because breast cancers are thought to arise from specific cell subpopulations of mammary epithelia, we studied the effect of parity on the transcriptome and the differentiation/proliferation potential of specific luminal and basal mammary cells in mice. Methods: Mammary epithelial cell subpopulations (luminal Sca1-, luminal Sca1+, basal stem/progenitor, and basal myoepithelial cells) were isolated by flow cytometry from parous and age-matched virgin mice and examined by using a combination of unbiased genomics, bioinformatics, in vitro colony formation, and in vivo limiting dilution transplantation assays. Specific findings were further investigated with immunohistochemistry in entire glands of parous and age-matched virgin mice. Results: Transcriptome analysis revealed an upregulation of differentiation genes and a marked decrease in the Wnt/Notch signaling ratio in basal stem/progenitor cells of parous mice. Separate bioinformatics analyses showed reduced activity for the canonical Wnt transcription factor LEF1/TCF7 and increased activity for the Wnt repressor TCF3. This finding was specific for basal stem/progenitor cells and was associated with downregulation of potentially carcinogenic pathways and a reduction in the proliferation potential of this cell subpopulation in vitro and in vivo. As a possible mechanism for decreased Wnt signaling in basal stem/progenitor cells, we found a more than threefold reduction in the expression of the secreted Wnt ligand Wnt4 in total mammary cells from parous mice, which corresponded to a similar decrease in the proportion of Wnt4-secreting and estrogen/progesterone receptor-positive cells. Because recombinant Wnt4 rescued the proliferation defect of basal stem/progenitor cells in vitro, reduced Wnt4 secretion appears to be causally related to parity-induced alterations of basal stem/progenitor cell properties in mice. Conclusions: By revealing that parity induces differentiation and downregulates the Wnt/Notch signaling ratio and the in vitro and in vivo proliferation potential of basal stem/progenitor cells in mice, our study sheds light on the long-term consequences of an early pregnancy. Furthermore, it opens the door to future studies assessing whether inhibitors of the Wnt pathway may be used to mimic the parity-induced protective effect against breast cancer. http://breast-cancer-research.com/content/15/2/R36 Fabienne Meier-Abt Emanuela Milani Tim Roloff Heike Brinkhaus Stephan Duss Dominique Meyer Ina Klebba Piotr Balwierz Erik van Nimwegen Mohamed Bentires-Alj Breast Cancer Research 2013, null:R36 2013-04-29T00:00:00Z doi:10.1186/bcr3419 Parity protects through altered gene expression <p>Early parity in mice alters the genomic signature of a distinct subset of mammary epithelial cells by inducing differentiation and reducing proliferation, ultimately protecting against breast cancer.</p> /content/figures/bcr3419-toc.gif Breast Cancer Research 1465-5411 ${item.volume} R36 2013-04-29T00:00:00Z XML Initially discovered as an estrogen-responsive gene in breast cancer cell lines, anterior gradient 2 (AGR2) is a developmentally regulated gene belonging to the protein disulfide isomerase (PDI) gene family. Developmentally, AGR2 is expressed in the mammary gland in an estrogen-dependent manner, and AGR2 knockout and overexpression mouse models indicate that the gene promotes lobuloalveolar development by stimulating cell proliferation. Although AGR2 overexpression alone seems insufficient for breast tumorigenesis in mice, several lines of investigations suggest that AGR2 promotes breast tumorigenesis. Overexpression of AGR2 in several breast cancer cell lines increases cell survival in clonogenic assays and cell proliferation, whereas AGR2 loss of function leads to decreased cell cycle progression and cell death. In addition, AGR2 was shown to promote metastasis of breast epithelial cells in an in vivo metastasis assay. As a PDI, AGR2 is thought to be involved in the unfolded protein response that alleviates endoplasmic reticulum stress. Since cancer has to overcome proteotoxic stress due to excess protein production, AGR2 may be one of many pro-survival factors recruited to assist in protein folding or degradation or both. When AGR2 is secreted, it plays a role in cellular adhesion and dissemination of metastatic tumor cells. In breast cancer, AGR2 expression is associated with estrogen receptor (ER)-positive tumors; its overexpression is a predictor of poor prognosis. The AGR2 gene is directly targeted by ER-alpha, which is preferentially bound in tumors with poor outcome. Whereas aromatase inhibitor therapy decreases AGR2 expression, tamoxifen acts as an agonist of AGR2 expression in ER-positive tumors, perhaps contributing to tamoxifen resistance. AGR2 is also overexpressed in a subset of ER-negative tumors. Furthermore, AGR2 expression is associated with the dissemination of metastatic breast cancer cells and can be used as a marker to identify circulating tumor cells and metastatic cells in sentinel lymph nodes. In conclusion, AGR2 is a promising drug target in breast cancer and may serve as a useful prognostic indicator as well as a marker of breast cancer metastasis. http://breast-cancer-research.com/content/15/2/204 Michael Salmans Fang Zhao Bogi Andersen Breast Cancer Research 2013, null:204 2013-04-24T00:00:00Z doi:10.1186/bcr3408 /content/figures/bcr3408-toc.gif Breast Cancer Research 1465-5411 ${item.volume} 204 2013-04-24T00:00:00Z XML