Dietary energy restriction inhibits estrogen-induced mammary, but not pituitary, tumorigenesis in the ACI rat.

Because of the suggested role of energy consumption and the well-documented role of estrogens in the etiology of breast cancer, we have examined the effect of a 40% restriction of dietary energy consumption on the ability of administered 17beta-estradiol (E2) to induce mammary tumorigenesis in female ACI rats. Experiments herein test the hypothesis that at least part of the inhibitory effect of energy restriction on mammary tumorigenesis is exerted downstream of potential effects of dietary manipulation on the production of estrogens by the ovaries. Ovary-intact ACI rats were fed a control or a 40% energy-restricted diet and were either treated continuously with E2 from subcutaneous Silastic tubing implants or received no hormone treatment. Mammary cancers rapidly developed in E2-treated rats fed the control diet; within 216 days of initiation of E2 treatment 100% of the population at risk exhibited palpable mammary tumors. Dietary energy restriction markedly inhibited E2-induced mammary tumorigenesis, as evidenced by significant reductions in cancer incidence and tumor burden as well as a significant increase in the latency to the appearance of the first palpable cancer. The inhibitory actions of dietary energy restriction on E2-induced mammary tumorigenesis were associated with an inhibition of E2-stimulated mammary cell proliferation. However, this inhibition was insufficient to block induction of lobuloalveolar hyperplasia or appearance of focal regions of atypical epithelial hyperplasia. These data suggest that dietary energy restriction inhibits E2-induced mammary cancer by attenuating or retarding the progression of atypical hyperplasia to carcinoma. Expression of progesterone receptor (PR) was up-regulated within the focal regions of atypical hyperplasia and the carcinomas induced by E2, regardless of whether the rats were fed the control or energy-restricted diet. However, circulating progesterone was reduced by dietary energy restriction, suggesting a possible mechanism for inhibition of mammary tumorigenesis. Dietary energy restriction did not inhibit the ability of administered E2 to induce prolactin (PRL)-producing pituitary tumors and associated hyperprolactinemia, indicating that the inhibitory effects of dietary energy restriction on mammary tumorigenesis are tissue specific and independent of circulating E2 and PRL.     

Inheritance and site of expression of genes controlling susceptibility to mammary cancer in an inbred rat model

An inbred rat model for genetically controlled susceptibility to chemically induced mammary cancer has been established. Wistar-Furth (W/Fu) rats were found to be more susceptible to 7,12-dimethylbenz(a)anthracene-induced mammary tumors than were Fischer (F344) rats. The susceptibilities of various F1, F2, and backcross generations of these strains were examined for susceptibility to 7,12-dimethylbenz(a)anthracene-induced mammary tumors. The data suggest that susceptibility is inherited as a dominant trait. Both a single locus autosomal model and an X-linked model have been ruled out. However, the data support the hypothesis that complete susceptibility is controlled by any one of a group of independently segregating genes; i.e., any one gene of this group is both necessary and sufficient to induce maximal susceptibility. It is not known if these genes are identical or different. In order to identify the role of these genes we asked if they were expressed in the mammary epithelial cells themselves or elsewhere in the rat. Chimeric animals were produced by transplanting mammary cells from either W/Fu or F344 rats into the white interscapular fat pad of female W/Fu X F344 F1 rats. One month after transplantation the animals were treated with 7,12-dimethylbenz(a)anthracene and then palpated weekly for tumor development at the graft site. Tumors developed more rapidly and in greater total frequency at sites grafted with W/Fu mammary cells. This result suggests that the genes controlling inherited susceptibility are expressed in the mammary cells. The role of these genes is now under investigation. We have thus far shown that they do not control carcinogen metabolism or activation.     

Tamoxifen induces regression of estradiol-induced mammary cancer in the ACI.COP-Ept2 rat model

The ACI rat is a unique model of human breast cancer in that mammary cancers are induced by estrogen without carcinogens, irradiation, xenografts or transgenic manipulations. We sought to characterize mammary cancers in a congenic variant of the ACI rat, the ACI.COP-Ept2. All rats with estradiol implants developed mammary cancers in 5–7 months. Rats bearing estradiol-induced mammary cancers were treated with tamoxifen for three weeks. Tamoxifen reduced tumor mass, measured by magnetic resonance imaging, by 89%. Tumors expressed estrogen receptors (ER), progesterone receptor (PR), and Erbb2. ERα and PR were overexpressed in tumor compared to adjacent non-tumor mammary gland. Thus, this model is highly relevant to hormone responsive human breast cancers.     

Genetic susceptibility to prostate cancer: a review

A genetic component in prostate cancer has been recognized since decades. Through numerous epidemiological and molecular biological studies, much evidence has accumulated in favor of a significant but heterogeneous hereditary component in prostate cancer (PCa) susceptibility. Since the mapping of a high-penetrant PCa susceptibility locus at 1q24–25, much attention has been paid to the identification of PCa susceptibility genes. So far, seven loci have been mapped, and at three of these loci, genes have been cloned and mutations identified. Yet their role in hereditary and sporadic disease is still under debate and probably very modest. Although research on hereditary prostate cancer has improved our knowledge of the genetic etiology of the disease, still a lot of questions remain unanswered. Here, we aim to review the genetic epidemiological and molecular biological research in the field of hereditary prostate cancer and the problems that are encountered with this research.     

Genetic resistance to mammary tumorigenesis in a mouse strain with high murine mammary tumor virus expression

Although II-TES mice release large amounts of murine mammary tumor virus (MMTV) in milk, they are resistant to mammary tumorigenesis. High mammary tumor incidence was observed in (BALB/ca X II-TES)F1 and (C57BL/6N X II-TES)F1, whereas no mammary tumors developed in BALB/ca X OZ-F)F1. Mammary tumors developed in 68% of (OZ-F X (OZ-F X II-TES)F1 and 45% of (II-TES X (OZ-F X II-TES)F1). These results suggest that the II-TES mouse carries a recessive gene for mammary tumor resistance which does not inhibit MMTV release, and two independent dominant mammary tumor promoting genes which are inhibited by the resistant gene.     

Conditions controlling long-term proliferation of Brown Norway rat promyelocytic leukemia in vitro: primary growth stimulation by microenvironment and establishment of an autonomous Brown Norway 'leukemic stem cell line'

Conditions for in vitro long-term maintenance and proliferation of the Brown Norway (BN) rat myelocytic leukemia cell (BNML) are described. During a primary culture of leukemic rat marrow, a few leukemic cells proliferated and were initially dependent on an adherent cell population but later acquired the capability of independent growth. A wild BN leukemic stem cell line has been maintained in vitro for several months, without noticeable phenotypic alterations. The doubling time of the cultured cells was 40 h. The cells were promyelocytes. The cytochemical markers of the original BN leukemia cells were preserved. The cultured cell line transferred leukemia exclusively to BN rats. Wistar and BDIX rats were resistant. The virulence of cultured leukemic cell was measured by shortened survival times after transplantation in animals of a fixed number of leukemic cells. The role of bone marrow microenvironment in the initiation of long-term growth is discussed.     

Five loci, SLT1 to SLT5, controlling the susceptibility to spontaneously occurring lung cancer in mice

A series of linkage studies was previously conducted to identify quantitative trait loci associated with chemically induced lung tumors. However, little is known of genetic susceptibility to spontaneously occurring lung tumorigenesis (SLT) in mice. In this study, we did a whole-genome linkage disequilibrium analysis for susceptibility to SLT in mice using approximately 135,900 single-nucleotide polymorphisms (SNPs) from the Roche and Genomic Institute of the Novartis Research Foundation SNP databases. A common set of 13 mouse strains was used, including 10 resistant strains (129X1/SvJ, AKR/J, C3H/HeJ, C57BL/6J, DBA/2J, NZB/BlnJ, CAST/EiJ, SPRET/EiJ, SM/J, and LP/J) and 3 susceptible strains (A/J, BALB/cJ, and NZW/LaCJ). Fisher exact test was used to assess the association between individual SNPs and susceptibility to SLT. Five regions, SLT1 to SLT5, were mapped on chromosomes 6, 7, 8, 19, and X, respectively. SLT1 to SLT5 showed a significant association with SLT under the empirical threshold (P < or = 0.004) derived from permutation tests. SNP versus SNP association tests indicated that these SLT regions were unlikely to be caused by population substructure. Thus, SLT1 to SLT5 seem to be novel loci controlling the susceptibility to spontaneously occurring lung cancer in mice. Our results provide, for the first time, an insight into the genetic control of spontaneously occurring lung tumorigenesis.     

Fine mapping reveals multiple loci and a possible epistatic interaction within the mammary carcinoma susceptibility quantitative trait locus, Mcs5

To identify high-frequency, low-penetrance breast cancer modifier genes, we have developed a rat genetic model that uses the Wistar-Kyoto (WKy) inbred strain, resistant to developing 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis, as a congenic donor and the susceptible Wistar-Furth (WF) strain as the recipient. Here, data from congenic rat lines containing smaller WKy genomic intervals of the Mcs5 quantitative trait locus region are presented to fine map three independently acting Mcs5 subloci. WKy-homozygous females from congenic lines defining Mcs5a, Mcs5b, and Mcs5c averaged, respectively, 4.0 +/- 0.4, 11.6 +/- 0.6, and 3.5 +/- 0.4 mammary carcinomas per rat. These phenotypic values are statistically different from the WF-homozygous phenotype value of 8.0 +/- 0.4, which is the baseline phenotype used for these experiments. We identified a likely Mcs5a x Mcs5b epistatic interaction that results in masking the increased susceptibility effect of the Mcs5b WKy allele by the Mcs5a WKy allele. We also provide evidence for a Mcs5a x Mcs5c interaction that is synergistic to decrease mammary carcinoma susceptibility below the additive effects of WKy alleles at each locus independently. The Mcs5 subloci are currently localized to 1.0, 7.5, and 4.5 Mb of rat chromosome 5, and the orthologous regions are on human chromosome 9 and mouse chromosome 4. These loci will provide unbiased candidate gene loci for evaluation in human case-control association studies.     

Relationships between cellular superoxide dismutase and susceptibility to chemically induced cancer in the rat mammary gland

Increasing evidence suggests a role for reactive free radicaloxygen species in the multi-stage events of chemical carcino-genesis.We hypothesized that variations in the level of super-oxidedismutase (SOD), a major endogenous antioxidant enzyme, mayaccount in part for variations in susceptibility to cancer inducedby polycyclic aromatic hydrocarbons (PAH). The SOD activityof mammary epithelial cells from rats with varying susceptibilityto dimethylbenz[a]anthracene (DMBA)-induced breast cancer wasassayed. Ageing, pregnancy and previous multiple pregnanciesreduce susceptibility of Sprague Dawley female rats to DMBA.These decreases in susceptibility were correlated with increasedlevels of SOD activity. Only minor differences in SOD activitywas observed in mammary epithelium of genetic strains of ratswith differences in susceptibility to DMBA. These data suggestthat, in models where physiological differences may accountfor variations in effectiveness of PAH to induce mammary cancer,SOD activity is inversely correlated with breast cancer susceptibilityand support the hypothesis that cancer susceptibility may bepartially mediated through reactive free radical oxygen intermediates.     

Requirement of essential fatty acid for mammary tumorigenesis in the rat

In an attempt to determine the requirement of essential fatty acid for dimethylbenz(a)anthracene-induced mammary tumorigenesis, rats were fed diets containing different levels of linoleate: 0.5, 1.1, 1.7, 2.2, 3.5, 4.4, 8.5, or 11.5%. Each diet contained 20% of fat by weight, with varying amounts of coconut oil and corn oil added to achieve the desired levels of linoleate. Mammary tumorigenesis was very sensitive to linoleate intake and increased proportionately in the range of 0.5 to 4.4% of dietary linoleate. Regression analysis indicated that a breakpoint occurred at 4.4%, beyond which there was a very poor linear relationship, suggesting the possibility of a plateau. From the intersection of the regression lines in both the upper and lower ranges, the level of linoleate required to elicit the maximal tumorigenic response was estimated to be around 4%. The differences in tumor yield could not be correlated with changes in prostaglandin E concentration in the mammary fat pads of normal animals maintained on similar diets, suggesting that linoleate may act by some other mechanism to stimulate mammary tumorigenesis.     

Mammary cancer resistance and precocious mammary differentiation in the WKY rat: identification of 2 quantitative trait loci

The COP and WKY rat strains are resistant to mammary cancer. It has shown previously that upon chemical carcinogen treatment, COP females exhibit mammary preneoplastic lesions which disappear within a few weeks. We show here that in similar conditions, WKY females do not exhibit any visible preneoplastic lesions. WKY females are characterized by precocious mammary tissue differentiation, including active expression of the beta-casein gene in young virgin females. This trait might be critical in resistance to mammary carcinogenesis of WKY rats. To test this hypothesis, we took advantage of 2 congenic strains that contain a limited chromosome segment of WKY origin, derived either from chromosome 5 or from chromosome 18, introgressed in the susceptible genetic background (SPRD-Cu3). Each of these congenic strains has been shown to be partially resistant to chemically induced mammary carcinogenesis (reduction in tumour multiplicity with respect to the susceptible SPRD-Cu3 rats). We show here that these 2 congenic strains also exhibit precocious mammary differentiation, though to a lower extent than the WKY females. The conclusion of this study is thus 2-fold: (i) eradication of preneoplastic lesions is not a general phenomenon in mammary cancer resistance; (ii) the same segment of rat chromosomes 5 or 18 that controls mammary cancer resistance also contains a quantitative trait locus imposing precocious mammary differentiation. These 2 traits are thus associated, supporting the hypothesis that there might be a cause-effect relationship between precocious mammary differentiation and cancer resistance.     

Genetic variants of 6q25 and breast cancer susceptibility: a two-stage fine mapping study in a Chinese population

A recent genome-wide association study identified a novel single nucleotide polymorphism (SNP), rs2046210, in the 6q25 region as a breast cancer susceptibility locus in Chinese and subsequently replicated in a multicenter study. Further fine-mapping of this region may help identify the potential causative SNPs of breast cancer. We employed a block-based fine mapping analysis to investigate the tagging SNPs in a 41 kb block with the marker-SNP rs2046210 in the 6q25 region, and also extended our study by including two potentially functional SNPs (rs2234693 and rs1801132) within the ESR1 gene by a two-stage case–control study with 1,792 breast cancer cases and 1,867 controls (878 cases and 900 controls in the testing set and 914 cases and 967 controls in the validation set). Significant associations with breast cancer risk were observed for rs1038304, rs6929137, rs2046210, and rs10484919 in the 41 kb block of the 6q25 region in the testing set after controlling multiple testing. Together with the validation set samples, these four SNPs were all significantly associated with increased risk of breast cancer (additive OR from 1.25 to 1.34, additive P from 4.84 × 10⁻⁶ to 7.17 × 10⁻⁹). After conditional regression and linkage disequilibrium analyses, rs6929137 and rs10484919 tend to be susceptible markers of breast cancer in this region and both of them were located at sites of histone modification according to the UCSC () genome database. Our results support that the 6q25 region is an important susceptibility region for breast cancer in Chinese women, and rs6929137 and rs10484919 are causative or marker SNPs for this region.     

CCND1基因870位点多态性同肿瘤遗传易感性关系的Meta分析

是其患肿瘤的一个遗传易感因素.     

Fine mapping of chromosome 5p15.33 identifies novel lung cancer susceptibility loci in Han Chinese

Genome‐wide association studies in European and Asian populations have consistently identified chromosome 5p15.33 as a lung cancer susceptibility region. To investigate further the genetic architecture of common variants in this region, we conducted a two‐stage fine‐mapping analysis discovered by targeted resequencing of 200 cases and 300 controls individually, and validated in multiethnic lung cancer Genome wide association studies (GWASs) with 12,843 cases and 12,639 controls. Two independent variants were identified in approximate conditional analysis with GCTA and consistently validated in lung cancer GWASs in both Asian and European populations. These were rs10054203 in TERT (resequencing: OR = 1.69, p = 2.70 × 10^?4; validation: OR = 1.34, p = 2.10 × 10^?23 for Asian, and OR = 1.09, p = 6.00 × 10^?3 for European), and rs397640 in CLPTM1L (resequencing: OR = 0.37, p = 1.19 × 10^?4; validation: OR = 0.75, p = 5.89 × 10^?8 for Asian, and OR = 0.90, p = 2.40 × 10^?2 for European). Expression quantitative trait loci analysis showed the risk allele (C) of rs10054203 was significantly associated with lower mRNA expression of CTD‐2245Ef15.3 (p = 0.019) and Tubulin Polymerization‐Promoting Protein (TPPP , p = 0.031) in 167 lung tissues. In conclusion, in this largest and first resequencing‐based fine‐mapping analysis of 5p15.33 region in Han Chinese, we identified two novel variants associated with lung cancer susceptibility. Further validation studies and functional work is required to confirm the roles of the newly discovered variants.     

Activation of certain N-arylacetamides and N-arylacetohydroxamic acids in relation to mammary gland tumorigenesis in the rat

This report describes activation of certain N-aryl-acetamides and N-arylacetohydroxamic acids and its relationship to mammary gland tumorigenesis. Evidence is presented that metabolic activation of N-2-fluorenylacetamide (2-FAA) by mixed function oxidase of liver microsomes is the primary requirement for tumor induction in the mammary gland by this compound in young adult female rats. Mammary gland microsomes of those rats appear incapable of N-hydroxylating 2-FAA. Mammary gland microsomes of lactating rats, however, are capable of converting small amounts of 2-FAA to N-hydroxy-2-FAA, which suggests that the ability to perform certain metabolic activation reactions may depend on the stage of development of the mammary gland which is hormonally regulated. According to a current theory of chemical carcinogenesis, N-arylacetohydroxamic acids would have to be activated to electrophilic reactants to become ultimate carcinogens. Three mechanisms by which such reactants could be generated from N-aryl-acetohydroxamic acids in the mammary gland are reviewed: 1) nonenzymatic acetylation; 2) enzymatic N-O-acetyl transfer to form N-acetoxyarylamines; 3) one-electron oxidation to nitroxyl free radicals. In addition, the potential role of the metabolically formed glucuronide of N-hydroxy-2-FAA in mammary gland tumorigenesis is discussed.     

Adenovirus type 9-induced tumorigenesis in the rat mammary gland related to sex hormonal state

Adenovirus type 9 was inoculated sc into newborn Wistar/Furth rats, divided into four groups: (1) six male rats, not treated further; (2) 11 male rats, castrated at 4 weeks of age; (3) 12 male rats, castrated at 4 weeks of age and subsequently treated repeatedly with estrogen; and (4) 12 female rats, not treated further. All of the rats in group 3 developed mammary hyperplasia and tumors (fibroadenomas and lipomas), in some cases with malignant histologic structure. Rats in group 4 developed similar mammary tumors, but with later appearance and significantly slower growth. A fifth group of rats, not virus inoculated but castrated and estrogen treated as in group 3, did not develop any demonstrable mammary lesions. The results show that the effects of the virus on the mammary gland are dependent upon an estrogenic background, which by itself cannot cause tumor development in males. It is suggested that viral DNA is incorporated into the cellular DNA in such a way that it influences the synthesis and/or activity of steroid receptors, triggering tumor development.     

Allele‐specific imbalance mapping at human orthologs of mouse susceptibility to colon cancer (Scc) loci

Colorectal cancer (CRC) can be classified into different types. Chromosomal instable (CIN) colon cancers are thought to be the most common type of colon cancer. The risk of developing a CIN‐related CRC is due in part to inherited risk factors. Genome‐wide association studies have yielded over 40 single nucleotide polymorphisms (SNPs) associated with CRC risk, but these only account for a subset of risk alleles. Some of this missing heritability may be due to gene‐gene interactions. We developed a strategy to identify interacting candidate genes/loci for CRC risk that utilizes both linkage and RNA‐seq data from mouse models in combination with allele‐specific imbalance (ASI) studies in human tumors. We applied our strategy to three previously identified CRC susceptibility loci in the mouse that show evidence of genetic interaction: Scc4, Scc5 and Scc13. 525 SNPs from genes showing differential expression in the mouse and/or a previous role in cancer from the literature were evaluated for allele‐specific imbalance in 194 paired human normal/tumor DNAs from CIN‐related CRCs. One hundred three SNPs showing suggestive evidence of ASI (31 variants with uncorrected p values < 0.05) were genotyped in a validation set of 296 paired DNAs. Two variants in SNX10 (SCC13) showed significant evidence of allelic selection after multiple comparisons testing. Future studies will evaluate the role of these variants in combination with interacting genetic partners in colon cancer risk in mouse and humans.     

Genetic control of resistance to chemically induced mammary adenocarcinogenesis in the rat

Fifty-day-old female rats of a series of outbred (i.e., SD) and inbred (i.e., NSD, WF, LEW, F344, ACI, and COP) strains were exposed to a single dose of either of two highly effective mammary chemical carcinogens, 7,12-dimethylbenz[a]anthracene (DMBA) or 1-methyl-1-nitrosourea (MNU), to determine the characteristic number of mammary adenocarcinomas induced/rat for each strain. Female rats of the inbred NSD, WF, and LEW strains were found to be as highly susceptible to DMBA exposure as the randomly outbred SD strain (i.e., greater than 2 mammary adenocarcinomas/rat develop). Inbred female F344 and ACI rats were found to be much less susceptible to DMBA induced mammary adenocarcinogenesis (i.e., less than 1.2 mammary adenocarcinomas/rat). In contrast to all the other inbred strains, the female COP rat was unique in that it is essentially completely resistant to all attempts to induce mammary adenocarcinomas by either DMBA or MNU exposure. Genetic breeding analysis demonstrated that the resistance of the mammary epithelium of the female COP rat to DMBA and MNU is due to the mendelian inheritance of a dominant, autosomal genetic allele. The inheritance of a single copy of this resistance allele is able to prevent both the DMBA and MNU induced development of mammary adenocarcinomas in F1 hybrids produced by cross-breeding COP to the highly susceptible NSD animal.     

Chromosome mapping of multiple loci affecting the genetic predisposition to rat liver carcinogenesis

Previous studies on (BNxF344)F1 (BFF1) rat model of genetic predisposition to hepatocarcinogenesis led to the identification, in BFF1xF344 backcross progeny, of two hepatocarcinogenesis susceptibility (Hcs) and three resistance (Hcr) loci affecting the progression of neoplastic liver nodules. To evaluate the presence of other hepatocarcinogenesis-related loci in the BFF1 genome, nodule induction by resistant hepatocyte model in 116 male BFF2 rats 32 weeks after initiation with diethylnitrosamine was subjected to quantitative trait loci analysis. The rats were typed with 179 genetic markers, and linkage analysis identified three loci on chromosomes 1, 16, and 6, in significant linkage with nodule mean volume (V), volume fraction, and number, respectively, and two loci on chromosomes 4 and 8 in suggestive linkage with V. These loci were differently positioned with respect to Hcs and Hcr loci mapped previously in backcross rats. On the basis of phenotypic and allele distribution patterns of BFF2 rats, loci on chromosomes 1 and 16 were identified as Hcs3 and Hcs4, and loci on chromosomes 4, 8, and 6 as Hcr4, Hcr5, and Hcr6. Additive interactions occurred between Hcs3 and Hcs4, and Hcr4 and a locus on chromosome 3 with less than suggestive linkage with V. All of the loci were in chromosomal regions syntenic to mouse and/or human chromosomal segments showing allelic gain or loss in hepatocellular carcinomas. These data indicate that inheritance of predisposition to rat liver tumor is characterized by the interplay of several genetic factors and suggest some possible mechanisms of polygenic control of human liver cancer.