title: Pathways contributing to development of spontaneous mammary tumors in BALB/c-Trp53+/- mice.
abstract: Mutation and loss of function in p53 are common features among human breast cancers. Here we use BALB/c-Trp53+/- mice as a model to examine the sequence of events leading to mammary tumors. Mammary gland proliferation rates were similar in both BALB/c-Trp53+/- mice and wild-type controls. In addition, sporadic mammary hyperplasias were rare in BALB/c-Trp53+/- mice and not detectably different from those of wild-type controls. Among the 28 mammary tumors collected from BALB/c-Trp53+/- mice, loss of heterozygosity for Trp53 was detected in more than 90% of invasive mammary tumors. Transplantation of Trp53+/- ductal hyperplasias also indicated an association between loss of the wild-type allele of Trp53 and progression to invasive carcinomas. Therefore, loss of p53 function seems to be a rate-limiting step in progression. Moreover, expression of biomarkers such as estrogen receptor alpha, progesterone receptor, Her2/Neu, and activated Notch1 varied among mammary tumors, suggesting that multiple oncogenic lesions collaborate with loss of p53 function. Expression of biomarkers was retained when tumor fragments were transplanted to syngeneic hosts. Tumors expressing solely luminal or basal keratins were also observed (27 and 11%, respectively), but the largest class of tumors expressed both luminal and basal keratins (62%). Overall, this panel of transplantable tumors provides a resource for detailed evaluation of the cell lineages undergoing transformation and preclinical testing of therapeutic agents targeting a variety of oncogenic pathways including cancer stem cells.
authors.affiliation: Department of Veterinary & Animal Science, 661 North Pleasant St., Integrated Sciences Bldg., University of Massachusetts-Amherst, Amherst, MA 01003-9286, USA.
authors.forename: Haoheng
authors.initials: H
authors.lastname: Yan
authors.forename: Anneke C
authors.initials: AC
authors.lastname: Blackburn
authors.forename: S Christine
authors.initials: SC
authors.lastname: McLary
authors.forename: Luwei
authors.initials: L
authors.lastname: Tao
authors.forename: Amy L
authors.initials: AL
authors.lastname: Roberts
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Xavier
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Dickinson
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seo
authors.forename: Richard B
authors.initials: RB
authors.lastname: Arenas
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Otis
authors.forename: Qing J
authors.initials: QJ
authors.lastname: Cao
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Lawlor
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Osborne
authors.forename: Frances S
authors.initials: FS
authors.lastname: Kittrell
authors.forename: Daniel
authors.initials: D
authors.lastname: Medina
authors.forename: D Joseph
authors.initials: DJ
authors.lastname: Jerry
mesh_terms: D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007633:Keratins / Q000378:metabolism; D019656:Loss of Heterozygosity / Q000235:genetics; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D007633:Keratins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D051880:Receptors, Notch; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; C524056:Erbb2 protein, mouse