Distinct Luminal-Type Mammary Carcinomas Arise from Orthotopic Trp53-Null Mammary Transplantation of Juvenile versus Adult Mice

Abstract

Age and physiological status, like 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 implanted during puberty (5 weeks) or at maturation (10 weeks) with syngeneic Trp53 null mammary tissue fragments and monitored for 1 year. Tumors arose sooner from adult hosts (AH) compared to juvenile hosts (JH). However, compared to AH tumors, JH tumors grew several times faster, were more perfused, exhibited a 2-fold higher mitotic index and were more highly positive for insulin-like growth factor receptor phosphorylation. Most tumors in each setting were 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 data sets. These data support the notion that age-associated host physiology greatly influences the intrinsic subtype of breast cancer.

Mammary Tumor–Derived Transplants as Breast Cancer Models to Evaluate Tumor–Immune Interactions and Therapeutic Responses

“…The resulting Trp53 null mammary chimeras undergo ductal outgrowth and most develop mammary tumors in the second year of life. These Trp53 null tumors are diverse in regard to histology, growth rate, composition and genomics (19,20,23,24). Randomly chosen vials of viably frozen fragments of Trp53 null primary tumors, designated as F0, were thawed and the fragments were bilaterally transplanted subcutaneously in 8-week-old athymic nude mice.…”

“…Trp53 mammary epithelial transplants undergo normal ductal morphogenesis but progress from outgrowths to ductal carcinoma in situ to invasive carcinomas over the course of the animal's lifespan. The resulting cancers are markedly heterogenous with regard to molecular profiles, expression of hormone receptors, and histology (17)(18)(19)(20), the spectrum of which recapitulate the diversity of human breast cancers (21,22). We recently showed that Trp53 null mammary tumors also exhibit distinct spatial TIL patterns (23), similar to those broadly described in human cancer (3).…”

From Mouse to Human: Cellular Morphometric Subtype Learned From Mouse Mammary Tumors Provides Prognostic Value in Human Breast Cancer

“…reported ( 8 ) that the transcriptional profiles of Trp53 null tumors could be classified into multiple molecular subtypes, namely, two basal-like, a luminal, a claudin-low, and a subtype unique to this model, which we also found ( 21 ). Notably, translation of transcriptomic signatures obtained from Trp53 null mammary tumor model informs the diversity of human BC ( 21 , 22 ). Conserved gene expression features exist between murine mammary carcinoma models and BC ( 7 ).…”