title: Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures.
abstract: Bypassing estrogen receptor (ER) signaling during development of endocrine resistance remains the most common cause of disease progression and mortality in breast cancer patients. To date, the majority of molecular research on ER action in breast cancer has occurred in cell line models derived from late stage disease. Here we describe patient-derived ER+ luminal breast tumor models for the study of intratumoral hormone and receptor action. Human breast tumor samples obtained from patients post surgery were immediately transplanted into NOD/SCID or NOD/SCID/ILIIrg(-/-) mice under estrogen supplementation. Five transplantable patient-derived ER+ breast cancer xenografts were established, derived from both primary and metastatic cases. These were assessed for estrogen dependency, steroid receptor expression, cancer stem cell content, and endocrine therapy response. Gene expression patterns were determined in select tumors ±estrogen and ±endocrine therapy. Xenografts morphologically resembled the patient tumors of origin, and expressed similar levels of ER (5-99 %), and progesterone and androgen receptors, over multiple passages. Four of the tumor xenografts were estrogen dependent, and tamoxifen or estrogen withdrawal (EWD) treatment abrogated estrogen-dependent growth and/or tumor morphology. Analysis of the ER transcriptome in select tumors revealed notable differences in ER mechanism of action, and downstream activated signaling networks, in addition to identifying a small set of common estrogen-regulated genes. Treatment of a naïve tumor with tamoxifen or EWD showed similar phenotypic responses, but relatively few similarities in estrogen-dependent transcription, and affected signaling pathways. Several core estrogen centric genes were shared with traditional cell line models. However, novel tumor-specific estrogen-regulated potential target genes, such as cancer/testis antigen 45, were uncovered. These results evoke the importance of mapping both conserved and tumor-unique ER programs in breast cancers. Furthermore, they underscore the importance of primary xenografts for improved understanding of ER+ breast cancer heterogeneity and development of personalized therapies.
authors: Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA.
authors: Peter
authors: P
authors: Kabos
authors: Jessica
authors: J
authors: Finlay-Schultz
authors: Chunling
authors: C
authors: Li
authors: Enos
authors: E
authors: Kline
authors: Christina
authors: C
authors: Finlayson
authors: Joshua
authors: J
authors: Wisell
authors: Christopher A
authors: CA
authors: Manuel
authors: Susan M
authors: SM
authors: Edgerton
authors: J Chuck
authors: JC
authors: Harrell
authors: Anthony
authors: A
authors: Elias
authors: Carol A
authors: CA
authors: Sartorius
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051927:CD24 Antigen / Q000378:metabolism; D016000:Cluster Analysis; D004967:Estrogens / Q000008:administration & dosage* / Q000502:physiology; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D059467:Transcriptome; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051927:CD24 Antigen; D004967:Estrogens; D018960:Hyaluronan Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; C497889:CD24 protein, human; C497483:CD44 protein, human; C508053:ERBB2 protein, human