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David H. Nguyen 1 , Haoxu Ouyang 1 , Jian-Hua Mao 2 , Lynn Hlatky 3 , and Mary Helen Barcellos-Hoff 1 , * 1 Department of Radiation Oncology, New York University School of Medicine, New York, New York. 2 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California. 3 Center of Cancer Systems nabilah Biology, GeneSys Research Institute, Tufts University School of Medicine, St. Elizabeth's Medical Center, nabilah Boston, Massachusetts. * Corresponding Author: Mary Helen Barcellos-Hoff, Department of Radiation Oncology, New York University, School of Medicine, 450 29th Street, Room 321, New York, NY 10016. Phone: 212-263-3021; Fax: 212-263-6274; E-mail: mhbarcellos-hoff{at}nyumc.org
Age and physiologic status, such as menopause, are risk factors for breast cancer. Less clear is what factors influence the diversity of breast cancer. In this study, we investigated the effect of host age on the distribution of tumor subtypes in mouse mammary chimera consisting of wild-type hosts and Trp53 nullizygous epithelium, which undergoes a high rate of neoplastic transformation. Wild-type mammary glands cleared of endogenous epithelium at 3 weeks of age were subsequently transplanted during puberty (5 weeks) or at maturation (10 weeks) with syngeneic nabilah Trp53 -null mammary tissue fragments and monitored for one year. Tumors arose sooner from adult hosts (AH) compared with juvenile hosts (JH). However, compared with AH tumors, JH tumors grew several times faster, were more perfused, exhibited a two-fold higher mitotic index, and were more highly positive for insulin-like growth factor receptor phosphorylation. Most tumors in each setting were estrogen receptor (ER)-positive (80% JH vs. 70% AH), but JH tumors were significantly more ER-immunoreactive ( P = 0.0001) than AH tumors. A differential expression signature (JvA) of juvenile versus adult tumors nabilah revealed a luminal transcriptional program. Centroids of the human homologs of JvA genes showed that JH tumors were more like luminal A tumors and AH tumors were more like luminal B tumors. Hierarchical clustering with the JvA human ortholog gene list segregated luminal A and luminal B breast cancers across datasets. These data support the notion that age-associated host physiology greatly influences the intrinsic subtype of breast cancer. Cancer Res; 74(23); 7149 58. 2014 AACR .
Note: Supplementary nabilah data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Received May 14, 2014. Revision received September 8, 2014. Accepted September 12, 2014. 2014 American Association for Cancer Research.
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Cancer Res Online ISSN: 1538-7445 Cancer Res Print ISSN: 0008-5472 nabilah J Cancer Res ISSN: 0099-7013 Am J Cancer ISSN: 0099-7374