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Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses [Cell Biology] (2012)

Chiba, N., Comaills, V., Shiotani, B., Takahashi, F., Shimada, T., Tajima, K., Winokur, D., Hayashida, T., Willers, H., Brachtel, E., Vivanco, M. d. M., Haber, D. A., Zou, L., Maheswaran, S.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences

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Publikationsdatum: 2012-02-22

Beschreibung: Homeobox 9 (HOXB9), a nontransforming transcription factor overexpressed in breast cancer, alters tumor cell fate and promotes tumor progression and metastasis. Here we show that HOXB9 confers resistance to ionizing radiation by promoting DNA damage response. In nonirradiated cells, HOXB9 induces spontaneous DNA damage, phosphorylated histone 2AX and p53 binding protein 1 foci, and increases baseline ataxia telangiectasia mutated (ATM) phosphorylation. Upon ionizing radiation, ATM is hyperactivated in HOXB9-expressing cells during the early stages of the double-stranded DNA break (DSB) response, accelerating accumulation of phosphorylated histone 2AX, mediator of DNA-damage checkpoint 1, and p53 binding protein 1, at DSBs and enhances DSB repair. The effect of HOXB9 on the response to ionizing radiation requires the baseline ATM activity before irradiation and epithelial-to-mesenchymal transition induced by TGF-β, a HOXB9 transcriptional target. Our results reveal the impact of a HOXB9–TGF-β–ATM axis on checkpoint activation and DNA repair, suggesting that TGF-β may be a key factor that links tumor microenvironment, tumor cell fate, DNA damage response, and radioresistance in a subset of HOXB9-overexpressing breast tumors.

Schlagwort(e): Breast Cancer Special Feature

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells [Genetics] (2012)

Herschkowitz, J. I., Zhao, W., Zhang, M., Usary, J., Murrow, G., Edwards, D., Knezevic, J., Greene, S. B., Darr, D., Troester, M. A., Hilsenbeck, S. G., Medina, D., Perou, C. M., Rosen, J. M.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences

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Publikationsdatum: 2012-02-22

Beschreibung: The claudin-low subtype is a recently identified rare molecular subtype of human breast cancer that expresses low levels of tight and adherens junction genes and shows high expression of epithelial-to-mesenchymal transition (EMT) genes. These tumors are enriched in gene expression signatures derived from human tumor-initiating cells (TICs) and human mammary stem cells. Through cross-species analysis, we discovered mouse mammary tumors that have similar gene expression characteristics as human claudin-low tumors and were also enriched for the human TIC signature. Such claudin-low tumors were similarly rare but came from a number of distinct mouse models, including the p53 null transplant model. Here we present a molecular characterization of 50 p53 null mammary tumors compared with other mouse models and human breast tumor subtypes. Similar to human tumors, the murine p53 null tumors fell into multiple molecular subtypes, including two basal-like, a luminal, a claudin-low, and a subtype unique to this model. The claudin-low tumors also showed high gene expression of EMT inducers, low expression of the miR-200 family, and low to absent expression of both claudin 3 and E-cadherin. These murine subtypes also contained distinct genomic DNA copy number changes, some of which are similarly altered in their cognate human subtype counterpart. Finally, limiting dilution transplantation revealed that p53 null claudin-low tumors are highly enriched for TICs compared with the more common adenocarcinomas arising in the same model, thus providing a unique preclinical mouse model to investigate the therapeutic response of TICs.

Schlagwort(e): Breast Cancer Special Feature

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737 [Medical Sciences] (2012)

Oakes, S. R., Vaillant, F., Lim, E., Lee, L., Breslin, K., Feleppa, F., Deb, S., Ritchie, M. E., Takano, E., Ward, T., Fox, S. B., Generali, D., Smyth, G. K., Strasser, A., Huang, D. C. S., Visvader, J. E., Lindeman, G. J.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences

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Publikationsdatum: 2012-02-22

Beschreibung: Overexpression of the prosurvival protein BCL-2 is common in breast cancer. Here we have explored its role as a potential therapeutic target in this disease. BCL-2, its anti-apoptotic relatives MCL-1 and BCL-XL, and the proapoptotic BH3-only ligand BIM were found to be coexpressed at relatively high levels in a substantial proportion of heterogeneous breast tumors, including clinically aggressive basal-like cancers. To determine whether the BH3 mimetic ABT-737 that neutralizes BCL-2, BCL-XL, and BCL-W had potential efficacy in targeting BCL-2–expressing basal-like triple-negative tumors, we generated a panel of primary breast tumor xenografts in immunocompromised mice and treated recipients with either ABT-737, docetaxel, or a combination. Tumor response and overall survival were significantly improved by combination therapy, but only for tumor xenografts that expressed elevated levels of BCL-2. Treatment with ABT-737 alone was ineffective, suggesting that ABT-737 sensitizes the tumor cells to docetaxel. Combination therapy was accompanied by a marked increase in apoptosis and dissociation of BIM from BCL-2. Notably, BH3 mimetics also appeared effective in BCL-2–expressing xenograft lines that harbored p53 mutations. Our findings provide in vivo evidence that BH3 mimetics can be used to sensitize primary breast tumors to chemotherapy and further suggest that elevated BCL-2 expression constitutes a predictive response marker in breast cancer.

Schlagwort(e): Breast Cancer Special Feature

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling [Medical Sciences] (2012)

Kristensen, V. N., Vaske, C. J., Ursini–Siegel, J., Van Loo, P., Nordgard, S. H., Sachidanandam, R., Sorlie, T., Warnberg, F., Haakensen, V. D., Helland, A., Naume, B., Perou, C. M., Haussler, D., Troyanskaya, O. G., Borresen–Dale, A.–L.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences

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Publikationsdatum: 2012-02-22

Beschreibung: We use an integrated approach to understand breast cancer heterogeneity by modeling mRNA, copy number alterations, microRNAs, and methylation in a pathway context utilizing the pathway recognition algorithm using data integration on genomic models (PARADIGM). We demonstrate that combining mRNA expression and DNA copy number classified the patients in groups that provide the best predictive value with respect to prognosis and identified key molecular and stromal signatures. A chronic inflammatory signature, which promotes the development and/or progression of various epithelial tumors, is uniformly present in all breast cancers. We further demonstrate that within the adaptive immune lineage, the strongest predictor of good outcome is the acquisition of a gene signature that favors a high T-helper 1 (Th1)/cytotoxic T-lymphocyte response at the expense of Th2-driven humoral immunity. Patients who have breast cancer with a basal HER2-negative molecular profile (PDGM2) are characterized by high expression of protumorigenic Th2/humoral-related genes (24–38%) and a low Th1/Th2 ratio. The luminal molecular subtypes are again differentiated by low or high FOXM1 and ERBB4 signaling. We show that the interleukin signaling profiles observed in invasive cancers are absent or weakly expressed in healthy tissue but already prominent in ductal carcinoma in situ, together with ECM and cell-cell adhesion regulating pathways. The most prominent difference between low and high mammographic density in healthy breast tissue by PARADIGM was that of STAT4 signaling. In conclusion, by means of a pathway-based modeling methodology (PARADIGM) integrating different layers of molecular data from whole-tumor samples, we demonstrate that we can stratify immune signatures that predict patient survival.

Schlagwort(e): Breast Cancer Special Feature

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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5

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Subtype and pathway specific responses to anticancer compounds in breast cancer [Systems Biology] (2012)

Heiser, L. M., Sadanandam, A., Kuo, W.-L., Benz, S. C., Goldstein, T. C., Ng, S., Gibb, W. J., Wang, N. J., Ziyad, S., Tong, F., Bayani, N., Hu, Z., Billig, J. I., Dueregger, A., Lewis, S., Jakkula, L., Korkola, J. E., Durinck, S., Pepin, F., Guan, Y., Purdom, E., Neuvial, P., Bengtsson, H., Wood, K. W., Smith, P. G., Vassilev, L. T., Hennessy, B. T., Greshock, J., Bachman, K. E., Hardwicke, M. A., Park, J. W., Marton, L. J., Wolf, D. M., Collisson, E. A., Neve, R. M., Mills, G. B., Speed, T. P., Feiler, H. S., Wooster, R. F., Haussler, D., Stuart, J. M., Gray, J. W., Spellman, P. T.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences

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Publikationsdatum: 2012-02-22

Beschreibung: Breast cancers are comprised of molecularly distinct subtypes that may respond differently to pathway-targeted therapies now under development. Collections of breast cancer cell lines mirror many of the molecular subtypes and pathways found in tumors, suggesting that treatment of cell lines with candidate therapeutic compounds can guide identification of associations between molecular subtypes, pathways, and drug response. In a test of 77 therapeutic compounds, nearly all drugs showed differential responses across these cell lines, and approximately one third showed subtype-, pathway-, and/or genomic aberration-specific responses. These observations suggest mechanisms of response and resistance and may inform efforts to develop molecular assays that predict clinical response.

Schlagwort(e): Breast Cancer Special Feature

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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6

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Transducin-like enhancer protein 1 mediates estrogen receptor binding and transcriptional activity in breast cancer cells [Applied Biological Sciences] (2012)

Holmes, K. A., Hurtado, A., Brown, G. D., Launchbury, R., Ross-Innes, C. S., Hadfield, J., Odom, D. T., Carroll, J. S.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences

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Publikationsdatum: 2012-02-22

Beschreibung: Estrogen receptor (ER) binds to distal enhancers within the genome and requires additional factors, such as the Forkhead protein FoxA1, for mediating chromatin interactions. We now show that the human Groucho protein, Transducin-like enhancer protein 1 (TLE1), positively assists some ER-chromatin interactions, a role that is distinct from its general role as a transcriptional repressor. We show that specific silencing of TLE1 inhibits the ability of ER to bind to a subset of ER binding sites within the genome, a phenomenon that results in perturbations in phospho-RNA Pol II recruitment. Furthermore, TLE1 is essential for effective ER-mediated cell division. We have discovered a distinct role for TLE1, as a necessary transcriptional component of the ER complex, where it facilitates ER-chromatin interactions.

Schlagwort(e): Breast Cancer Special Feature

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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The HOXB7 protein renders breast cancer cells resistant to tamoxifen through activation of the EGFR pathway [Medical Sciences] (2012)

Jin, K., Kong, X., Shah, T., Penet, M.-F., Wildes, F., Sgroi, D. C., Ma, X.-J., Huang, Y., Kallioniemi, A., Landberg, G., Bieche, I., Wu, X., Lobie, P. E., Davidson, N. E., Bhujwalla, Z. M., Zhu, T., Sukumar, S.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences

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Publikationsdatum: 2012-02-22

Beschreibung: Multiple factors including long-term treatment with tamoxifen are involved in the development of selective estrogen receptor (ER) modulator resistance in ERα-positive breast cancer. Many underlying molecular events that confer resistance are known but a unifying theme is yet to be revealed. In this report, we provide evidence that HOXB7 overexpression renders MCF-7 cells resistant to tamoxifen via cross-talk between receptor tyrosine kinases and ERα signaling. HOXB7 is an ERα-responsive gene. Extended treatment of MCF-7 cells with tamoxifen resulted in progressively increasing levels of HOXB7 expression, along with EGFR and EGFR ligands. Up-regulation of EGFR occurs through direct binding of HOXB7 to the EGFR promoter, enhancing transcriptional activity. Finally, higher expression levels of HOXB7 in the tumor significantly correlated with poorer disease-free survival in ERα-positive patients with breast cancer on adjuvant tamoxifen monotherapy. These studies suggest that HOXB7 acts as a key regulator, orchestrating a major group of target molecules in the oncogenic hierarchy. Functional antagonism of HOXB7 could circumvent tamoxifen resistance.

Schlagwort(e): Breast Cancer Special Feature

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Mechanistic insight into Myc stabilization in breast cancer involving aberrant Axin1 expression [Cell Biology] (2012)

Zhang, X., Farrell, A. S., Daniel, C. J., Arnold, H., Scanlan, C., Laraway, B. J., Janghorban, M., Lum, L., Chen, D., Troxell, M., Sears, R.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences

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Publikationsdatum: 2012-02-22

Beschreibung: High expression of the oncoprotein Myc has been linked to poor outcome in human tumors. Although MYC gene amplification and translocations have been observed, this can explain Myc overexpression in only a subset of human tumors. Myc expression is in part controlled by its protein stability, which can be regulated by phosphorylation at threonine 58 (T58) and serine 62 (S62). We now report that Myc protein stability is increased in a number of breast cancer cell lines and this correlates with increased phosphorylation at S62 and decreased phosphorylation at T58. Moreover, we find this same shift in phosphorylation in primary breast cancers. The signaling cascade that controls phosphorylation at T58 and S62 is coordinated by the scaffold protein Axin1. We therefore examined Axin1 in breast cancer and report decreased AXIN1 expression and a shift in the ratio of expression of two naturally occurring AXIN1 splice variants. We demonstrate that this contributes to increased Myc protein stability, altered phosphorylation at S62 and T58, and increased oncogenic activity of Myc in breast cancer. Thus, our results reveal an important mode of Myc activation in human breast cancer and a mechanism contributing to Myc deregulation involving unique insight into inactivation of the Axin1 tumor suppressor in breast cancer.

Schlagwort(e): Breast Cancer Special Feature

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen [Medical Sciences] (2012)

Mendes-Pereira, A. M., Sims, D., Dexter, T., Fenwick, K., Assiotis, I., Kozarewa, I., Mitsopoulos, C., Hakas, J., Zvelebil, M., Lord, C. J., Ashworth, A.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences

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Publikationsdatum: 2012-02-22

Beschreibung: Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1, CLPP, GPRC5D, NAE1, NF1, NIPBL, NSD1, RAD21, RARG, SMC3, and UBA3) and also a set of genes whose silencing causes sensitivity to this endocrine agent (C10orf72, C15orf55/NUT, EDF1, ING5, KRAS, NOC3L, PPP1R15B, RRAS2, TMPRSS2, and TPM4). Multiple individual genes, including NF1, a regulator of RAS signaling, also correlate with clinical outcome after tamoxifen treatment.

Schlagwort(e): Breast Cancer Special Feature

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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