Progression of pregnancy-dependent mouse mammary tumors after long dormancy periods. Involvement of Wnt pathway activation.
Mouse mammary tumor virus (LA) induces pregnancy-dependent mammary tumors that progress toward autonomy. Here we show that in virgin females, pregnancy-dependent tumor transplants are able to remain dormant for up to 300 days. During that period, these tumors synthesize DNA, express high levels of estrogen and progesterone receptors (ER+PR+) and are able to resume growth after hormone stimulation. Surprisingly, in a subsequent transplant generation, all these tumors are fully able to grow in virgin females, they express low levels of ER and PR (ER-PR-) and have a monoclonal origin; i.e., show all of the features we have described previously in pregnancy-independent tumors. Histologically, mouse mammary tumor virus (LA)-induced tumors are morphologically similar to genetically engineered mouse (GEM) mammary tumors that overexpress genes belonging to the Wnt pathway. Interestingly, in the virus-induced neoplasias, pregnancy-independent passages arising after a dormant phase usually display a lower level of glandular differentiation together with epithelial cell trans-differentiation, a specific feature associated to Wnt pathway activation. In addition, dormancy can lead to the specific selection of Int2/Fgf3 mutated and overexpressing cells. Therefore, our results indicate that during hormone-dependent tumor dormancy, relevant changes in cell population occur, allowing rapid progression after changes in the animal internal milieu.
ILEX-CONICET, División Medicina Experimental, Instituto de Investigaciones Hematológicas e Instituto de Estudios Oncológicos, Academia Nacional de Medicina, J.A. Pacheco de Melo 3081, (1425) Buenos Aires, Argentina.
Albana
A
Gattelli
María Cecilia
MC
Cirio
Ana
A
Quaglino
Carolina
C
Schere-Levy
Natalia
N
Martinez
María
M
Binaghi
Roberto P
RP
Meiss
Lucio H
LH
Castilla
Edith C
EC
Kordon
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002454:Cell Differentiation; D002455:Cell Division; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D051518:Fibroblast Growth Factor 3; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000472:pathogenicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D051154:Wnt2 Protein
C489197:Fgf3 protein, mouse; D051518:Fibroblast Growth Factor 3; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D051154:Wnt2 Protein; D005346:Fibroblast Growth Factors