%0 Journal Article %J Sci Rep %D 2015 %T Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment. %A Zhang, Pengju %A Lo, Alvin %A Huang, Yurong %A Huang, Ge %A Liang, Guozhou %A Mott, Joni %A Karpen, Gary H %A Blakely, Eleanor A %A Bissell, Mina J %A Barcellos-Hoff, Mary Helen %A A Snijders %A Jiang-Hua Mao %K Animals %K Breast Neoplasms %K Cell Line, Tumor %K Cytokines %K Female %K Genetic Predisposition to Disease %K Mice %K Mice, Inbred BALB C %K Neoplasms, Radiation-Induced %K Quantitative Trait Loci %K Risk Factors %K Transforming Growth Factor beta1 %K Tumor Microenvironment %X

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.

%B Sci Rep %V 5 %P 8919 %8 2015 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25747469?dopt=Abstract %R 10.1038/srep08919 %0 Journal Article %J Integr Biol (Camb) %D 2011 %T Gene transcriptional networks integrate microenvironmental signals in human breast cancer. %A Xu, Ren %A Jiang-Hua Mao %K Breast Neoplasms %K Cadherins %K Cytokines %K Extracellular Matrix %K Extracellular Matrix Proteins %K Female %K Gene Expression Profiling %K Gene Regulatory Networks %K Humans %K Integrins %K Intercellular Signaling Peptides and Proteins %K Mammary Glands, Human %K Oligonucleotide Array Sequence Analysis %K Receptor, Platelet-Derived Growth Factor beta %K Receptors, Cytokine %K Transforming Growth Factor beta %K Tumor Microenvironment %X

A significant amount of evidence shows that microenvironmental signals generated from extracellular matrix (ECM) molecules, soluble factors, and cell-cell adhesion complexes cooperate at the extra- and intracellular level. This synergetic action of microenvironmental cues is crucial for normal mammary gland development and breast malignancy. To explore how the microenvironmental genes coordinate in human breast cancer at the genome level, we have performed gene co-expression network analysis in three independent microarray datasets and identified two microenvironment networks in human breast cancer tissues. Network I represents crosstalk and cooperation of ECM microenvironment and soluble factors during breast malignancy. The correlated expression of cytokines, chemokines, and cell adhesion proteins in Network II implicates the coordinated action of these molecules in modulating the immune response in breast cancer tissues. These results suggest that microenvironmental cues are integrated with gene transcriptional networks to promote breast cancer development.

%B Integr Biol (Camb) %V 3 %P 368-74 %8 2011 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21165486?dopt=Abstract %R 10.1039/c0ib00087f