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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., (©2010 AACR.)

Studies of cellular interactions are critical to the understanding of tumorigenesis. Although many studies have demonstrated a monoclonal composition of advanced neoplasms in humans and mice, the clonal composition of smaller, antecedent lesions has been studied less thoroughly. To examine the clonal development of breast cancer, we generated chimeric mammary glands using mouse mammary epithelium with an inherited predisposition for neoplasia. Analysis of whey acidic protein-transforming growth factor-alpha transgenic mouse mammary glands, chimeric for two different cell lineage markers, revealed that mammary ducts and alveoli are polyclonal, and putative early preneoplastic lesions, hyperplastic alveolar nodules (HANs), frequently are polyclonal. Furthermore, the chimeric patch patterns in individual HANs were similar to the patterns observed in pregnant chimeric mammary glands. Thus, polyclonality in HANs appears to reflect persistence of the polyclonal architecture of ducts and/or alveoli, suggesting that hyperplasia formation can be the result of non-cell autonomous local tissue microenvironmental influences on groups of cells, rather than clonal progression of a single initiated cell.

Activating mutation of the Kras oncogene is the most frequent and perhaps the earliest genetic alteration associated with pancreatic cancer. To examine the link between mutant Kras and exocrine pancreatic cancer, we generated transgenic mice carrying an elastase-mutant Kras transgene, which targets expression to pancreatic acinar cells. Most elastase-Kras founder mice displayed perinatal pancreatic acinar cell hyperplasia and dysplasia. However, adult mice in two surviving lineages displayed preinvasive pancreatic neoplastic lesions with ductal morphology, thereby providing a unique mouse model in which lesion histotype and initiating genetic alteration overlap with the human disease. Our findings suggest that Kras mutation is associated with development of early stage duct-like lesions in pancreas, but that additional alterations must accompany progression to malignancy.

Deregulated expression of transforming growth factor alpha (TGF-alpha) or c-myc has been implicated in the genesis of human breast cancer. To better characterize the role of these molecules in this disease, we generated transgenic mice that express TGF-alpha or c-myc under control of the mouse whey acidic protein (WAP) promoter. We then compared the resulting mammary gland neoplasia in these mice and in previously described mice expressing a metallothionein-driven TGF-alpha transgene. Nonvirgin female mice in all transgenic lineages developed mammary tumors with 100% incidence but variable latency. Among TGF-alpha lines, mean survival time correlated with the level of transgene expression, and the average life spans of high-expressing WAP-TGF-alpha and WAP-c-myc mice were similarly reduced. The majority of TGF-alpha-induced tumors were relatively well-differentiated adenomas and adenocarcinomas; in contrast, WAP-c-myc tumors were poorly differentiated, solid carcinomas with a minority of adenocarcinomas. Most TGF-alpha and all c-myc-induced tumors were transplantable, but lung metastases were infrequently observed in all transgenic lines. WAP-TGF-alpha-induced tumors, in marked contrast to those induced by WAP-c-myc, displayed frequent induction of cyclin D1 mRNA, suggesting that expression of this gene may complement that of TGF-alpha during mammary tumor development. Expression of TGF-alpha also induced precocious development of pregnant glands and delayed or inhibited mammary involution. As a result, multiparious MT-TGF-alpha and especially WAP-TGF-alpha females accumulated large numbers of hyperplastic alveolar nodules that resembled the more differentiated TGF-alpha-induced tumors. Finally, coexpression of WAP-c-myc and WAP-TGF-alpha transgenes markedly decreased tumor latency, increased tumor growth, and even induced mammary tumors in virgin female and male mice. These findings provide further evidence for the importance of deregulated TGF-alpha expression in multistage carcinogenesis, and they suggest that in the mammary gland the mechanism of TGF-alpha-induced transformation may depend on postlactational survival of differentiated epithelium. They also provide evidence of a potent tumorigenic collaboration between TGF-alpha and c-myc in mammary epithelium.