title: Distinct luminal-type mammary carcinomas arise from orthotopic Trp53-null mammary transplantation of juvenile versus adult mice.
abstract: 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 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 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.
authors.affiliation: Department of Radiation Oncology, New York University School of Medicine, New York, New York.
authors.forename: David H
authors.initials: DH
authors.lastname: Nguyen
authors.affiliation: Department of Radiation Oncology, New York University School of Medicine, New York, New York.
authors.forename: Haoxu
authors.initials: H
authors.lastname: Ouyang
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.affiliation: Center of Cancer Systems Biology, GeneSys Research Institute, Tufts University School of Medicine, St. Elizabeth's Medical Center, Boston, Massachusetts.
authors.forename: Lynn
authors.initials: L
authors.lastname: Hlatky
authors.affiliation: Department of Radiation Oncology, New York University School of Medicine, New York, New York. mhbarcellos-hoff@nyumc.org.
authors.forename: Mary Helen
authors.initials: MH
authors.lastname: Barcellos-Hoff
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D004848:Epithelium / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D042361:Mammary Glands, Human / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D011960:Receptors, Estrogen; D017451:Receptors, Somatomedin; D016159:Tumor Suppressor Protein p53