Polyomavirus middle T-induced mammary intraepithelial neoplasia outgrowths: single origin, divergent evolution, and multiple outcomes.
The development of models to investigate the pathobiology of premalignant breast lesions is a critical prerequisite for development of breast cancer prevention and early intervention strategies. Using tissue transplantation techniques, we modified the widely used polyomavirus middle T (PyV-mT) transgenic mouse model of breast cancer to study the premalignant stages of tumorigenesis. Premalignant atypical lesions were isolated from PyV-mT transgenic mice and used to generate two sets of three mammary intraepithelial neoplasia (MIN) outgrowth lines. Investigation of these six unique lines, each of which fulfills the criteria for MIN, has provided new information regarding the biology of PyV-mT-induced neoplasia. Although expression of the PyV-mT transgene was the primary initiating event for all lines, they exhibited different tumor latencies, metastatic potentials, and morphologies. Six distinguishable morphologic patterns of differentiation were identified within the premalignant outgrowths that are likely to represent several tumorigenic pathways. Further, several tumor phenotypes developed from each line and the tumors developing from the six lines had different metastatic potentials. These observations are consistent with the hypothesis that distinct pathways of PyV-mT-initiated neoplastic progression lead to different outcomes with respect to latency and metastasis. The MIN outgrowth lines share several characteristics with precursors of human breast cancer including the observation that gene expression profiles of tumors are more similar to those of the MIN outgrowth line outgrowth from which they developed than to other tumors. These lines provide an opportunity to study the full range of events occurring secondary to PyV-mT expression in the mammary gland.
Department of Medicine, UCSD Cancer Center, School of Medicine, University of California-San Diego, La Jolla, CA, USA.
Jeannie E
JE
Maglione
Erik T
ET
McGoldrick
Lawrence J T
LJ
Young
Ruria
R
Namba
Jeffrey P
JP
Gregg
Lin
L
Liu
Drew
D
Moghanaki
Lesley G
LG
Ellies
Alexander D
AD
Borowsky
Robert D
RD
Cardiff
Carol L
CL
MacLeod
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000737:chemistry*; D002278:Carcinoma in Situ / Q000473:pathology* / Q000821:virology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D018450:Disease Progression; D019143:Evolution, Molecular; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology; D008321:Mammary Glands, Animal / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000473:pathology* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D005810:Multigene Family; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000737:chemistry; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes
D000952:Antigens, Polyomavirus Transforming; D009841:Oligonucleotides; D011960:Receptors, Estrogen; D012313:RNA; D004247:DNA