@article {219, title = {Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015}, pages = {8919}, abstract = {

The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGFβ1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFβ1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.

}, keywords = {Animals, Breast Neoplasms, Cell Line, Tumor, Cytokines, Female, Genetic Predisposition to Disease, Mice, Mice, Inbred BALB C, Neoplasms, Radiation-Induced, Quantitative Trait Loci, Risk Factors, Transforming Growth Factor beta1, Tumor Microenvironment}, issn = {2045-2322}, doi = {10.1038/srep08919}, author = {Zhang, Pengju and Lo, Alvin and Huang, Yurong and Huang, Ge and Liang, Guozhou and Mott, Joni and Karpen, Gary H and Blakely, Eleanor A and Bissell, Mina J and Barcellos-Hoff, Mary Helen and A Snijders and Jiang-Hua Mao} } @article {209, title = {An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival.}, journal = {Oncotarget}, volume = {5}, year = {2014}, month = {2014 Jun 30}, pages = {4011-25}, abstract = {

The concept that a breast cancer patient{\textquoteright}s menstrual stage at the time of tumor surgery influences risk of metastases remains controversial. The scarcity of comprehensive molecular studies of menstrual stage-dependent fluctuations in the breast provides little insight in this observation. To gain a deeper understanding of the biological changes in mammary tissue and blood during the menstrual cycle and to determine the influence of environmental exposures, such as low-dose ionizing radiation (LDIR), we used the mouse to characterize estrous-cycle variations in mammary gene transcripts by RNA-sequencing, peripheral white blood cell (WBC) counts and plasma cytokine levels. We identified an estrous-variable and hormone-dependent gene cluster enriched for Type-1 interferon genes. Cox regression identified a 117-gene signature of interferon-associated genes, which correlated with lower frequencies of metastasis in breast cancer patients. LDIR (10cGy) exposure had no detectable effect on mammary transcripts. However, peripheral WBC counts varied across the estrous cycle and LDIR exposure reduced lymphocyte counts and cytokine levels in tumor-susceptible mice. Our finding of variations in mammary Type-1 interferon and immune functions across the estrous cycle provides a mechanism by which timing of breast tumor surgery during the menstrual cycle may have clinical relevance to a patient{\textquoteright}s risk for distant metastases.

}, keywords = {Animals, Disease-Free Survival, Estrous Cycle, Female, Humans, Interferons, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Metastasis, RNA, Messenger}, issn = {1949-2553}, doi = {10.18632/oncotarget.2148}, author = {A Snijders and Langley, Sasha and Jiang-Hua Mao and Bhatnagar, Sandhya and Bjornstad, Kathleen A and Rosen, Chris J and Lo, Alvin and Huang, Yurong and Blakely, Eleanor A and Karpen, Gary H and Bissell, Mina J 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} }