@article {238, title = {Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer.}, journal = {Breast Cancer Res}, volume = {18}, year = {2016}, month = {2016}, pages = {70}, abstract = {

BACKGROUND: High mitotic activity is associated with the genesis and progression of many cancers. Small molecule inhibitors of mitotic apparatus proteins are now being developed and evaluated clinically as anticancer agents. With clinical trials of several of these experimental compounds underway, it is important to understand the molecular mechanisms that determine high mitotic activity, identify tumor subtypes that carry molecular aberrations that confer high mitotic activity, and to develop molecular markers that distinguish which tumors will be most responsive to mitotic apparatus inhibitors.

METHODS: We identified a coordinately regulated mitotic apparatus network by analyzing gene expression profiles for 53 malignant and non-malignant human breast cancer cell lines and two separate primary breast tumor datasets. We defined the mitotic network activity index (MNAI) as the sum of the transcriptional levels of the 54 coordinately regulated mitotic apparatus genes. The effect of those genes on cell growth was evaluated by small interfering RNA (siRNA).

RESULTS: High MNAI was enriched in basal-like breast tumors and was associated with reduced survival duration and preferential sensitivity to inhibitors of the mitotic apparatus proteins, polo-like kinase, centromere associated protein E and aurora kinase designated GSK462364, GSK923295 and GSK1070916, respectively. Co-amplification of regions of chromosomes 8q24, 10p15-p12, 12p13, and 17q24-q25 was associated with the transcriptional upregulation of this network of 54 mitotic apparatus genes, and we identify transcription factors that localize to these regions and putatively regulate mitotic activity. Knockdown of the mitotic network by siRNA identified 22 genes that might be considered as additional therapeutic targets for this clinically relevant patient subgroup.

CONCLUSIONS: We define a molecular signature which may guide therapeutic approaches for tumors with high mitotic network activity.

}, issn = {1465-542X}, doi = {10.1186/s13058-016-0728-y}, author = {Hu, Zhi and Jiang-Hua Mao and Curtis, Christina and Huang, Ge and Gu, Shenda and Heiser, Laura and Lenburg, Marc E and Korkola, James E and Bayani, Nora and Samarajiwa, Shamith and Seoane, Jose A and A Dane, Mark and Esch, Amanda and Feiler, Heidi S and Wang, Nicholas J and Hardwicke, Mary Ann and Laquerre, Sylvie and Jackson, Jeff and W Wood, Kenneth and Weber, Barbara and Spellman, Paul T and Aparicio, Samuel and Wooster, Richard and Caldas, Carlos and Gray, Joe W} } @article {78, title = {Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e45394}, abstract = {

High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, \<10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGFβ-signaling, and (d) inappropriate expression of developmental genes. One month after LD exposure, the two strains showed opposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p = 0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p\<0.0001). There is concordant direction of expression in the LD-exposed sensitive mouse strain, in biomarkers of human DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice are similar to the tissue mechanisms that determine poor-survival in breast cancer patients. We observed non-linearity of the LD responses providing molecular evidence against the LNT risk model and obtained new evidence that LD responses are strongly influenced by genotype. Our findings suggest that the biological assumptions concerning the mechanisms by which LD radiation is translated into breast cancer risk should be reexamined and suggest a new strategy to identify genetic features that predispose or protect individuals from LD-induced breast cancer.

}, keywords = {Animals, Breast Neoplasms, Dose-Response Relationship, Radiation, Female, Genetic Predisposition to Disease, Genomic Instability, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Radiation, Ionizing, RNA, Messenger, Survival Analysis, Transcription, Genetic, Tumor Microenvironment}, issn = {1932-6203}, doi = {10.1371/journal.pone.0045394}, author = {A Snijders and Marchetti, Francesco and Bhatnagar, Sandhya and Duru, Nadire and Ju Han and Hu, Zhi and Jiang-Hua Mao and Gray, Joe W and Wyrobek, Andrew J} } @article {167, title = {The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer.}, journal = {Breast Cancer Res}, volume = {12}, year = {2010}, month = {2010}, pages = {R18}, abstract = {

INTRODUCTION: HJURP (Holliday Junction Recognition Protein) is a newly discovered gene reported to function at centromeres and to interact with CENPA. 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 CENPA 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.

}, keywords = {Biomarkers, Tumor, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Disease-Free Survival, DNA-Binding Proteins, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Oligonucleotide Array Sequence Analysis, Predictive Value of Tests, Prognosis, RNA Interference, RNA, Messenger}, issn = {1465-542X}, doi = {10.1186/bcr2487}, author = {Hu, Zhi and Huang, Ge and Sadanandam, Anguraj and Gu, Shenda and Lenburg, Marc E and Pai, Melody and Bayani, Nora and Blakely, Eleanor A and Gray, Joe W and Jiang-Hua Mao} }