Pathways Contributing to Development of Spontaneous Mammary Tumors in BALB/c- Trp53 +/− Mice

Haoheng Yan, Anneke C. Blackburn, S. Christine McLary, Luwei Tao, Amy L. Roberts, Elizabeth A. Xavier, Ellen S. Dickinson, Jae Hong Seo, Richard B. Arenas, Christopher N. Otis, Qing J. Cao, Rebecca G. Lawlor (+4 others)
2010 American Journal of Pathology  
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
more » ... 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 ␣, 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. Compromised function of the p53 tumor suppressor pathway remains among the most common alterations found in cancers. 1,2 Although disruption of p53 function predisposes to a broad spectrum of malignancies, the breast epithelium seems exquisitely sensitive to proper p53 function. Polymorphisms in MDM2, CHK2, and ATM alter the stability and activity of p53 and have been linked to breast cancer risk in women. The activity of p53 has also been shown to be responsive to hormones in rodent models. 3-5 Exogenous estrogen and progesterone are sufficient to render the mammary epithelium resistant to carcinogen-induced tumors, mimicking the protective effect afforded by a full-term pregnancy, 6 and the p53 pathway participates in the hormone-induced protection. 7,8 Furthermore, breast cancer is the most prevalent tumor among women with Li-Fraumeni syndrome, which is most commonly associated with heterozygous mutations in TP53. 9 -11 Reduced dosage of the p53 gene has been associated with haploinsufficiency with respect to levels of p53 protein and activity, cell cycle arrest, apoptosis, and homology-directed DNA re-
doi:10.2353/ajpath.2010.090438 pmid:20110418 pmcid:PMC2832161 fatcat:ymp3aldsjbff5nd65zvxcqtu5u