TY - JOUR T1 - Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment. JF - Sci Rep Y1 - 2015 A1 - Zhang, Pengju A1 - Lo, Alvin A1 - Huang, Yurong A1 - Huang, Ge A1 - Liang, Guozhou A1 - Mott, Joni A1 - Karpen, Gary H A1 - Blakely, Eleanor A A1 - Bissell, Mina J A1 - Barcellos-Hoff, Mary Helen A1 - A Snijders A1 - Jiang-Hua Mao KW - Animals KW - Breast Neoplasms KW - Cell Line, Tumor KW - Cytokines KW - Female KW - Genetic Predisposition to Disease KW - Mice KW - Mice, Inbred BALB C KW - Neoplasms, Radiation-Induced KW - Quantitative Trait Loci KW - Risk Factors KW - Transforming Growth Factor beta1 KW - Tumor Microenvironment AB -

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.

VL - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25747469?dopt=Abstract ER - TY - JOUR T1 - Low-dose radiation cancer susceptibility models. JF - Aging (Albany NY) Y1 - 2015 A1 - Jiang-Hua Mao A1 - A Snijders KW - Dose-Response Relationship, Radiation KW - Genetic Predisposition to Disease KW - Humans KW - Models, Biological KW - Neoplasms, Radiation-Induced KW - Risk Factors VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26143074?dopt=Abstract ER - TY - JOUR T1 - CD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues JF - Cancer Discov Y1 - 2012 A1 - DeFilippis, Rosa Anna A1 - Hang Chang A1 - Dumont, Nancy A1 - Rabban, Joseph T A1 - Chen, Yunn-Yi A1 - Fontenay, Gerald V A1 - Berman, Hal K A1 - Gauthier, Mona L A1 - Zhao, Jianxin A1 - Hu, Donglei A1 - Marx, James J A1 - Tjoe, Judy A A1 - Ziv, Elad A1 - Febbraio, Maria A1 - Kerlikowske, Karla A1 - Parvin, Bahram A1 - Tlsty, Thea D KW - Adipocytes KW - Animals KW - Antigens, CD36 KW - Breast Neoplasms KW - Cell Differentiation KW - Female KW - Humans KW - Mammography KW - Mice KW - Mice, Knockout KW - Risk Factors KW - Signal Transduction KW - Stromal Cells AB -

UNLABELLED: Although high mammographic density is considered one of the strongest risk factors for invasive breast cancer, the genes involved in modulating this clinical feature are unknown. Tissues of high mammographic density share key histologic features with stromal components within malignant lesions of tumor tissues, specifically low adipocyte and high extracellular matrix (ECM) content. We show that CD36, a transmembrane receptor that coordinately modulates multiple protumorigenic phenotypes, including adipocyte differentiation, angiogenesis, cell-ECM interactions, and immune signaling, is greatly repressed in multiple cell types of disease-free stroma associated with high mammographic density and tumor stroma. Using both in vitro and in vivo assays, we show that CD36 repression is necessary and sufficient to recapitulate the above-mentioned phenotypes observed in high mammographic density and tumor tissues. Consistent with a functional role for this coordinated program in tumorigenesis, we observe that clinical outcomes are strongly associated with CD36 expression.

SIGNIFICANCE: CD36 simultaneously controls adipocyte content and matrix accumulation and is coordinately repressed in multiple cell types within tumor and high mammographic density stroma, suggesting that activation of this stromal program is an early event in tumorigenesis. Levels of CD36 and extent of mammographic density are both modifiable factors that provide potential for intervention.

VL - 2 IS - 9 ER - TY - JOUR T1 - A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice. JF - Nat Genet Y1 - 2006 A1 - To, Minh D A1 - Perez-Losada, Jesus A1 - Jiang-Hua Mao A1 - Hsu, Jeff A1 - Jacks, Tyler A1 - Balmain, Allan KW - Adenoma KW - Alleles KW - Animals KW - Carcinogens KW - Female KW - Genetic Predisposition to Disease KW - Lung Neoplasms KW - Male KW - Mice KW - Models, Genetic KW - Mutation KW - Oncogenes KW - Proto-Oncogene Proteins p21(ras) KW - Risk Factors KW - Urethane AB -

Pulmonary adenoma susceptibility 1 (Pas1) is the major mouse lung cancer susceptibility locus on chromosome 6 (ref. 1). Kras2 is a common target of somatic mutation in chemically induced mouse lung tumors and is a candidate Pas1 gene. M. spretus mice (SPRET/Ei) carry a Pas1 resistance haplotype for chemically induced lung tumors. We demonstrate that the SPRET/Ei Pas1 allele is switched from resistance to susceptibility by fixation of the parental origin of the mutant Kras2 allele. This switch correlates with low expression of endogenous Kras2 in SPRET/Ei. We propose that the Pas1 modifier effect is due to Kras2, and that a sensitive balance between the expression levels of wild-type and mutant alleles determines lung tumor susceptibility. These data demonstrate that cancer predisposition should also be considered in the context of somatic events and could have major implications for the design of human association studies to identify cancer susceptibility genes.

VL - 38 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/16823377?dopt=Abstract ER - TY - JOUR T1 - Factors affecting fetal weight distribution in women with type I diabetes. JF - BJOG Y1 - 2000 A1 - Johnstone, F D A1 - Jiang-Hua Mao A1 - Steel, J M A1 - Prescott, R J A1 - Hume, R KW - Birth Weight KW - Diabetes Mellitus, Type 1 KW - Female KW - Fetal Weight KW - Hemoglobin A, Glycosylated KW - Hemoglobinuria KW - Humans KW - Hypoglycemia KW - Infant, Newborn KW - Pregnancy KW - Pregnancy in Diabetics KW - Prospective Studies KW - Risk Factors KW - Scotland KW - Smoking AB -

OBJECTIVE: To identify factors independently affecting fetal weight in women with type I diabetes.

DESIGN: Prospectively recorded data in consecutive women with type I diabetes, between 1975-1992.

SETTING: Simpson Memorial Maternity Hospital, Edinburgh. Population Three hundred and two pregnancies with type I diabetes identified before pregnancy, with antenatal care and delivery in the Simpson Memorial Maternity Hospital, a singleton pregnancy, and the same diabetic physician.

METHODS: Normal ranges for birthweight were established for the total hospital population. All cases and the total population had pregnancy dating by ultrasound. The relation between standardised birthweight and explanatory variables was investigated using correlation analysis, t tests and chi2 tests as appropriate, and subsequently using multiple linear regression.

RESULTS: Standardised birthweight in cases, compared with the reference population, showed a unimodal, approximately normal distribution, markedly shifted to the right (mean + 1.26 SD). The most predictive variable was glycated haemoglobin concentration at 27-33 weeks, which explained 6.3% of the birthweight variance, while smoking explained 2.7% and maternal weight 2.0%. There was a trend towards a negative relationship with glycated haemoglobin concentration at 6-12 weeks. Smoking and glycated haemoglobin concentration were strongly intercorrelated.

CONCLUSIONS: Most of the variance in standardised birthweight remains unexplained, but glycated haemoglobin concentration at 27-33 weeks is the most powerful explanatory variable. Possible reasons why there is not a stronger relationship between markers of maternal glycaemia and birthweight are discussed.

VL - 107 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/10955432?dopt=Abstract ER -