Publications by authors named "Andrea Bilger"

15 Publications

  • Page 1 of 1

Estrogen Receptor-α Suppresses Liver Carcinogenesis and Establishes Sex-Specific Gene Expression.

Cancers (Basel) 2021 May 13;13(10). Epub 2021 May 13.

McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA.

Estrogen protects females from hepatocellular carcinoma (HCC). To determine whether this protection is mediated by classic estrogen receptors, we tested HCC susceptibility in estrogen receptor-deficient mice. In contrast to a previous study, we found that diethylnitrosamine induces hepatocarcinogenesis to a significantly greater extent when females lack , which encodes Estrogen Receptor-α. Relative to wild-type littermates, knockout females developed 9-fold more tumors. Deficiency of , which encodes Estrogen Receptor-β, did not affect liver carcinogenesis in females. Using microarrays and QPCR to examine estrogen receptor effects on hepatic gene expression patterns, we found that germline deficiency resulted in the masculinization of gene expression in the female liver. Six of the most dysregulated genes have previously been implicated in HCC. In contrast, deletion specifically in hepatocytes of conditional null female mice (in which Cre was expressed from the albumin promoter) resulted in the maintenance of female-specific liver gene expression. Wild-type adult females lacking ovarian estrogen due to ovariectomy, which is known to make females susceptible to HCC, also maintained female-specific expression in the liver of females. These studies indicate that mediates liver cancer risk, and its control of sex-specific liver gene expression involves cells other than hepatocytes.
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http://dx.doi.org/10.3390/cancers13102355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153146PMC
May 2021

Views From Patients With Cancer in the Setting of Unplanned Acute Care: Informing Approaches to Reduce Health Care Utilization.

JCO Oncol Pract 2020 11 23;16(11):e1291-e1303. Epub 2020 Jun 23.

Penn Center for Cancer Care Innovation at the Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Purpose: New oncology care delivery models that avoid preventable acute care are needed, yet it is unclear which interventions best meet the needs of patients and caregivers. Perspectives from patients who experienced unplanned acute care events may inform the successful development and implementation of care delivery models.

Methods: We performed a qualitative interview study of patients with solid tumors on active treatment who experienced the following 3 types of unplanned acute care events: emergency department visits, first hospitalizations, and multiple hospitalizations. Patients were prospectively recruited within a large academic health system from August 2018 to January 2019. Interviews followed a semi-structured guide developed from the Consolidated Framework for Implementation Research. The constant comparative approach was used to identify themes.

Results: Forty-nine patients were interviewed; 51% were men, 75% were non-Hispanic White, and the mean age was 57.4 years (standard deviation, 1.9 years). Fifty-five percent of patients had metastatic disease, and 33% had an Eastern Cooperative Oncology Group performance status of 3-4. We identified the following key themes: drivers of the decision to seek acute care, patients' emotional concerns that influence interactions with the oncology team, and strategies used to avoid acute care. Patients' recommendations for interventions included anticipatory guidance, peer support, improved triage methods, and enhanced symptom management. Patients preferred options for virtual and home-based outpatient care.

Conclusion: Patient-centered care models should focus on early delivery of supportive interventions that help patients and caregivers navigate the unexpected issues that come with cancer treatment. Patients advocate for proactive, multidisciplinary supportive interventions that enable home-based care and are led by the primary oncology team.
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http://dx.doi.org/10.1200/OP.20.00013DOI Listing
November 2020

A Mouse Model of Oropharyngeal Papillomavirus-Induced Neoplasia Using Novel Tools for Infection and Nasal Anesthesia.

Viruses 2020 04 16;12(4). Epub 2020 Apr 16.

McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53705, USA.

Human head and neck cancers that develop from the squamous cells of the oropharynx (Oropharyngeal Squamous Cell Carcinomas or OPSCC) are commonly associated with the papillomavirus infection. A papillomavirus infection-based mouse model of oropharyngeal tumorigenesis would be valuable for studying the development and treatment of these tumors. We have developed an efficient system using the mouse papillomavirus (MmuPV1) to generate dysplastic oropharyngeal lesions, including tumors, in the soft palate and the base of the tongue of two immune-deficient strains of mice. To maximize efficiency and safety during infection and endoscopy, we have designed a nose cone for isoflurane-induced anesthesia that takes advantage of a mouse's need to breathe nasally and has a large window for oral manipulations. To reach and infect the oropharynx efficiently, we have repurposed the Greer Pick allergy testing device as a virus delivery tool. We show that the Pick can be used to infect the epithelium of the soft palate and the base of the tongue of mice directly, without prior scarification. The ability to induce and track oropharyngeal papillomavirus-induced tumors in the mouse, easily and robustly, will facilitate the study of oropharyngeal tumorigenesis and potential treatments.
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http://dx.doi.org/10.3390/v12040450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232375PMC
April 2020

The human papillomavirus 16 E5 gene potentiates MmuPV1-Dependent pathogenesis.

Virology 2020 02 5;541:1-12. Epub 2019 Dec 5.

McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI, 53705-2275, United States. Electronic address:

The papillomavirus E5 gene contributes to transformation and tumorigenesis; however, its exact function in these processes and viral pathogenesis is unclear. While E5 is present in high-risk mucosotropic HPVs that cause anogenital and head and neck cancers, it is absent in cutaneous HPVs and the recently discovered mouse papillomavirus (MmuPV1), which causes papillomas and squamous cell carcinomas of the skin and mucosal epithelia in laboratory mice. We infected K14E5 transgenic mice, which express the high-risk mucosotropic HPV16 E5 gene in stratified epithelia, with MmuPV1 to investigate the effects of E5 on papillomavirus-induced pathogenesis. Skin lesions in MmuPV1-infected K14E5 mice had earlier onset, higher incidence, and reduced frequency of spontaneous regression compared to those in non-transgenic mice. K14E5 mice were also more susceptible to cervicovaginal cancers when infected with MmuPV1 and treated with estrogen compared to non-transgenic mice. Our studies support the hypothesis that E5 contributes to papillomavirus-induced pathogenesis.
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http://dx.doi.org/10.1016/j.virol.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024000PMC
February 2020

Perspectives and Practice in the Identification and Treatment of Opioid Use, Alcohol Use, and Depressive Disorders.

Psychiatr Serv 2019 10 12;70(10):940-943. Epub 2019 Jun 12.

Department of Psychiatry, Perelman School of Medicine (Wolk, Oslin), Department of Family Medicine and Community Health (Doubeni, Klusaritz, Bilger, Paterson), and Center for Public Health Initiatives (Klusaritz), all at the University of Pennsylvania, Philadelphia; Mental Illness Research, Education and Clinical Center, Cpl. Michael J. Crescenz Department of Veterans Affairs Medical Center, Philadelphia (Oslin).

Objective: Little research has focused on the treatment of adults with substance use disorders in primary care despite the high occurrence, morbidity, and mortality associated with these disorders.

Methods: An electronic survey was administered to primary care providers in a large health system to assess screening and treatment practices and comfort managing opioid use, alcohol use, and depressive disorders. A total of 146 providers completed the survey (32%).

Results: Providers were significantly less likely to screen for or treat opioid use disorders and alcohol use disorders, compared with depression. Providers reported feeling significantly less confident, less prepared, less expected to treat, less sure of the appropriateness of treating, and less able to navigate community resources in the treatment of opioid and alcohol use disorders, compared with depression.

Conclusions: Given the preponderance of substance use disorders in primary care, increased attention to equipping primary care providers to treat these conditions is warranted.
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http://dx.doi.org/10.1176/appi.ps.201800378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773501PMC
October 2019

Activating Mutations in Contribute to Anal Carcinogenesis in the Presence or Absence of HPV-16 Oncogenes.

Clin Cancer Res 2019 03 7;25(6):1889-1900. Epub 2018 Dec 7.

McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Purpose: Over 95% of human anal cancers are etiologically associated with high-risk HPVs, with HPV type 16 (HPV16) the genotype most commonly found. Activating mutations in the catalytic subunit of Phosphatidylinositol (3,4,5)-trisphosphate kinase (PI3K), encoded by the gene, are detected in approximately 20% of human anal cancers. We asked if common activating mutations in contribute to anal carcinogenesis using an established mouse model for anal carcinogenesis in which mice are topically treated with the chemical carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA). Mice expressing in their anal epithelium one of two activating mutations in genes, or , were monitored for anal carcinogenesis in the presence or absence of transgenes expressing the HPV16 E6 and E7 oncogenes.

Results: Both mutant forms of increased susceptibility to anal carcinogenesis in the absence of HPV16 oncogenes, and cooperated with HPV16 oncogenes to induce the highest level and earliest onset of anal cancers. The combination of HPV16 oncogenes and mutations led to anal cancers even in the absence of treatment with DMBA. We further observed that the investigational mTOR1/2 dual inhibitor, TAK-228, significantly reduced the size of anal cancer-derived tumor spheroids and reduced the growth rates of anal cancer-derived tumor grafts .

Conclusions: These data demonstrate that activating mutations in drive anal carcinogenesis together with HPV16 oncogenes, and that the PI3K/mTOR pathway is a relevant target for therapeutic intervention.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423984PMC
March 2019

Conceptualizing restorative justice for people with mental illnesses leaving prison or jail.

Am J Orthopsychiatry 2019 8;89(6):693-703. Epub 2018 Nov 8.

School of Social Work, College of Public Health, Temple University.

Individuals with psychiatric disabilities who are involved in the criminal justice system face a number of challenges to community integration upon release. There is a critical need to develop and evaluate interventions for these individuals that connect them to the community by enhancing naturalistic social connections and helping them to participate meaningfully in valued roles. The purposes of this article are to describe, provide a theoretical rationale, and propose a conceptual model for the use of a particular restorative justice model, circles of support and accountability, to meet this need. We describe the principles of restorative justice (repairing harm, stakeholder involvement, and the transformation of community and governmental roles and relationships) and how these map on to elements of the circles intervention. These elements include a focus on community participation, positive social support, democratic decision making, collective ownership of crime problems, and connection to community-based resources. We then suggest how changes in identity transformation, moral development and motivation, and collective efficacy might mediate relationships between these intervention elements and community integration outcomes. Finally, we encourage the systematic evaluation of the circles intervention for people with mental health conditions leaving custody and provide recommendations for policy and practice. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/ort0000316DOI Listing
April 2020

Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication.

Oncotarget 2017 Jul;8(27):44266-44280

Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.

EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both "on target" and "off target" mechanisms and is increasingly used to treat these viruses in organ transplant recipients. However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown. We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV-transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication. Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV-induced LPD in patients who have high EBV loads yet require continued immunosuppression.
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http://dx.doi.org/10.18632/oncotarget.17863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546479PMC
July 2017

Exploring Personal Medicine as Part of Self-Directed Care: Expanding Perspectives on Medical Necessity.

Psychiatr Serv 2016 08 1;67(8):883-9. Epub 2016 Apr 1.

Except for Ms. Maula, the authors are with the Department of Rehabilitation Sciences, Temple University, Philadelphia (e-mail: ). Ms. Maula is with the Mental Health Association of Southeastern Pennsylvania, Philadelphia.

Objective: Self-directed care (SDC) offers flexibility in and control over mental health services. This study examined the types of goods and services that individuals with serious mental illness request in an SDC intervention.

Methods: Data were from a randomized controlled trial that enrolled adult participants receiving Medicaid-reimbursed services, with two years of expenditures at the 50%-90% level of all Medicaid enrollees in the county and no hospitalizations within six months of the study. Data were analyzed for 60 participants randomly assigned to an SDC intervention, who were allowed to make requests for and purchase nontraditional goods and services through a noncapitated fund. Requests were coded by using the section on activities and participation of the World Health Organization's International Classification of Function, Disability, and Health (ICF) model. Descriptive statistics are presented for the categories of requests made by participants.

Results: The 60 participants made a total of 507 requests, representing 621 ICF codes. Requests ranged from 0 to 37 requests per person, with a mean of 8.45 requests. The average time to first request was 95.5 days. Most codes were in the area of self-care (19%) and general tasks and demands (19%). Among the 52 participants who made requests, the mean was 11.94 requests, which addressed an average of 5.60 unique needs.

Conclusions: Individuals with serious mental illness identified personal-medicine strategies to address needs that are currently unmet by traditional mental health services. Self-directed care may be a service delivery option that allows consumers to access their own personal medicine and better address their needs.
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http://dx.doi.org/10.1176/appi.ps.201500311DOI Listing
August 2016

Genetic background determines if Stat5b suppresses or enhances murine hepatocarcinogenesis.

Mol Carcinog 2015 Oct 17;54(10):959-70. Epub 2014 May 17.

McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.

Murine hepatocarcinogenesis requires growth hormone (GH). To determine if the GH-responsive transcription factor STAT5b (signal transducer and activator of transcription 5b) is also required, we compared the hepatic gene expression profiles of global Stat5b null mice to cancer-resistant mice mutant in the GH pathway-GH-deficient little and androgen receptor-null Tfm males. We found a high degree of overlap among Tfm, little, and Stat5b null males. The liver cancer susceptibility of global Stat5b null mice was assessed on three distinct genetic backgrounds: BALB/cJ (BALB), C57BL/6J (B6), and C3H/HeJ (C3H). The effect of Stat5b on hepatocarcinogenesis depended on the genetic background. B6 Stat5b null congenic males and females developed 2.4 times as many tumors as wild-type (WT) controls (P < 0.002) and the tumors were larger (P < 0.003). In BALB/c congenics, loss of STAT5b had no effect on either sex. C3H Stat5b null congenic males and females were resistant to liver cancer, developing 2.7- and 6-fold fewer tumors, respectively (P < 0.02, 0.01). These results provide the first example of a single gene behaving as both oncogene and tumor suppressor in a given tissue, depending only on the endogenous modifier alleles carried by different genetic backgrounds.
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http://dx.doi.org/10.1002/mc.22165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254363PMC
October 2015

Identification of susceptibility loci in a mouse model of KRASG12D-driven pancreatic cancer.

Cancer Res 2010 Nov 19;70(21):8398-406. Epub 2010 Oct 19.

McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.

Genetic background affects susceptibility to pancreatic ductal adenocarcinoma in the Ela-KRAS(G12D) mouse model. In this model, KRAS oncogene expression is driven by an elastase promoter in acinar cells of the pancreas on an FVB/NTac (FVB) background [FVB-Tg(Ela-KRAS(G12D))] with the transgene carried on the Y chromosome. Through linkage analysis of crosses between the C57BL/6J (B6), BALB/cJ (BALB), and DBA/2J (D2) inbred strains of mice and resistant FVB-Tg(Ela-KRAS(G12D)), we have identified six susceptibility loci that affect mean preinvasive lesion multiplicity. Markers on chromosome 2 segregated with high tumor multiplicity in all three strains; these loci were designated Prsq1-3 (pancreatic ras susceptibility quantitative trait loci 1-3; combined F2 and N2 LOD(W), 6.0, 4.1, and 2.7, respectively). Susceptibility loci on chromosome 4, designated Prsq4 and Prsq5, were identified in crosses between FVB transgenic mice and B6 or BALB mice (combined F2 and N2 LOD(W), 3.6 and 2.9, respectively). A marker on chromosome 12 segregated with tumor multiplicity in a BALB × FVB-Tg(Ela-KRAS(G12D)) cross and was designated Prsq6 (LOD(W), ∼2.5). B6-Chr Y(FVB-Tg(Ela-KRASG12D)) and BALB-Chr Y(FVB-Tg(Ela-KRASG12D)) consomics, which carry the KRAS transgene on the FVB Y chromosome on an otherwise inbred B6 or BALB background, developed ∼4-fold (B6) and ∼10-fold (BALB) more lesions than FVB-Tg(Ela-KRAS(G12D)) mice. By 12 months of age, 10% of BALB-Chr Y(FVB-Tg(Ela-KRASG12D)) mice developed invasive carcinomas. Our findings provide evidence that regions of chromosomes 2, 4, and 12 influence the development and progression of pancreatic neoplasms initiated by an oncogenic allele of KRAS in mice.
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http://dx.doi.org/10.1158/0008-5472.CAN-09-3980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141286PMC
November 2010

Predominant modifier of extreme liver cancer susceptibility in C57BR/cdJ female mice localized to 6 Mb on chromosome 17.

Carcinogenesis 2009 May 2;30(5):879-85. Epub 2009 Mar 2.

McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, 1400 University Avenue, Madison, WI 53706, USA.

Sex hormones influence the susceptibility of inbred mice to liver cancer. C57BR/cdJ (BR) females are extremely susceptible to spontaneous and chemically induced liver tumors, in part due to a lack of protection against hepatocarcinogenesis normally offered by ovarian hormones. BR males are also moderately susceptible, and the susceptibility of both sexes of BR mice to liver tumors induced with N,N-diethylnitrosamine relative to the resistant C57BL/6J (B6) strain is caused by two loci designated Hcf1 and Hcf2 (hepatocarcinogenesis in females) located on chromosomes 17 and 1, respectively. The Hcf1 locus on chromosome 17 is the predominant modifier of liver cancer in BR mice. To validate the existence of this locus and investigate its potential interaction with Hcf2, congenic mice for each region were generated. Homozygosity for the B6.BR(D17Mit164-D17Mit2) region resulted in a 4-fold increase in liver tumor multiplicity in females and a 4.5-fold increase in males compared with B6 controls. A series of 16 recombinants covering the entire congenic region was developed to further narrow the area containing Hcf1. Susceptible heterozygous recombinants demonstrated a 3- to 7-fold effect in females and a 1.5- to 2-fold effect in males compared with B6 siblings. The effect in susceptible lines completely recapitulated the susceptibility of heterozygous full-length chromosome 17 congenics and furthermore narrowed the location of the Hcf1 locus to a single region of the chromosome from 30.05 to 35.83 Mb.
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http://dx.doi.org/10.1093/carcin/bgp054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675651PMC
May 2009

Biologic study of the effects of octreotide-LAR on growth hormone in unresectable and metastatic hepatocellular carcinoma.

Clin Adv Hematol Oncol 2008 Jan;6(1):44-54

Department of Medicine, Section of Hematology and Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.

Background: Animal models suggest that growth hormone participates in hepatocarcinogenesis.

Objective: To correlate the effect of octreotide long-acting release (LAR) on insulin-like growth factor-I (IGF-I) and -II (IGF-II) with response and survival in patients with unresectable and metastatic hepatocellular carcinoma.

Methods: We conducted a phase II, single-institution trial of octreotide-LAR (30 mg intramuscularly every 4 weeks) in 15 patients while monitoring serum IGF-I and -II levels.

Results: Patients (median CLIP score 2, Okuda stage II, and ECOG performance status 1) were treated for a median of 2.0 cycles. No responses occurred. Median overall survival was 116 days (range, 27-937 days) and median progression-free survival was 60 days (range, 27-444 days). One patient had prolonged stable disease (16 months). There were no grade 4 and four grade 3 toxicities: abdominal cramping, elevated creatinine, diarrhea, and dyspnea. Median serum IGF-I decreased from baseline (42.2 ng/mL; range, 14.2-109 ng/mL) to day 29 (27.9 ng/mL; range, 5.7-71.1 ng/mL), and median serum IGF-II decreased from baseline (25,000 ng/mL; range, 12,400-93,600 ng/mL) to day 29 (18,400 ng/mL; range, 4,061-79,400 ng/mL; 2-sided P<.006 and P<.04, respectively; Wilcoxon signed rank test). This suppression did not correlate with clinical activity. Baseline serum IGF-I >30 ng/mL was associated with greater progression-free survival and overall survival (P=.0005 and P=.0173, respectively; 2-sided log-rank test).

Conclusions: Octreotide-LAR lowered serum IGF-I and -II levels; however, this lowering did not correlate with clinical activity. There were no responses, and progression-free survival and overall survival were similar to historical patients not on treatment. Baseline serum IGF-I predicted prognosis.
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January 2008

Widespread hyperplasia induced by transgenic TGFalpha in ApcMin mice is associated with only regional effects on tumorigenesis.

Carcinogenesis 2008 Sep 28;29(9):1825-30. Epub 2008 Feb 28.

Department of Oncology, McArdle Laboratory for Cancer Research, University ofWisconsin School of Medicine and Public Health, Madison, WI 53706, USA.

Using a mouse predisposed to neoplasia by a germ line mutation in Apc (Apc(Min)), we tested whether induced hyperplasia is sufficient to increase intestinal tumor multiplicity or size in the intestine. We found that hyperplasia in the jejunum correlated with a significant increase in tumor multiplicity. However, tumor multiplicity was unchanged in the hyperplastic colon. This result indicates that even an intestine predisposed to neoplasia can, in certain regions including the colon, accommodate net increased cell growth without developing more neoplasms. Where hyperplasia correlated with increased tumor multiplicity, it did not increase the size or net growth of established tumors. This result suggests that the event linking hyperplasia and neoplasia in the jejunum is tumor establishment. Two novel observations arose in our study: the multiple intestinal neoplasia (Min) mutation partially suppressed both mitosis and transforming growth factor alpha-induced hyperplasia throughout the intestine; and zinc treatment alone increased tumor multiplicity in the duodenum of Min mice.
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http://dx.doi.org/10.1093/carcin/bgn038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2547353PMC
September 2008

A potent modifier of liver cancer risk on distal mouse chromosome 1: linkage analysis and characterization of congenic lines.

Genetics 2004 Jun;167(2):859-66

McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.

The C3H/HeJ (C3H) and CBA/J (CBA) mouse strains are classical mouse models of cancer susceptibility, exhibiting high risks for both spontaneous and chemically induced liver cancer. By analysis of backcrosses and intercrosses between C3H or CBA and resistant B6 mice, we have mapped a potent modifier of hepatocellular carcinoma development to distal chromosome 1, linked to the marker D1Mit33 with combined LOD(W) scores of approximately 5.9 (C3H) and 6.5 (CBA). We previously identified this region as one of two that modify susceptibility in the more distantly related C57BR/cdJ (BR) strain. Congenic B6.C3H(D1Mit5-D1Mit17) and B6.BR(D1Mit5-D1Mit17) mice developed significantly more liver tumors than B6 mice did (6- to 13-fold, P < 10(-11), in males; 3- to 4-fold, P < 10(-3), in females). Thus, distal chromosome 1 carries one or more genes that are sufficient to confer susceptibility to liver cancer.
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http://dx.doi.org/10.1534/genetics.103.024521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1470923PMC
June 2004
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