
DOI . ORG {
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Title[redir]:
Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures | Breast Cancer Research and Treatment
Description:
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.
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Keywords {🔍}
cancer, breast, article, google, scholar, pubmed, cas, receptor, estrogen, res, cell, cells, xenografts, sartorius, tumor, human, progesterone, expression, therapy, usa, luminal, hormone, gene, molecular, stem, kabos, endocrine, tumors, receptors, treat, research, resistance, tamoxifen, cancers, osborne, oncol, dois, horwitz, content, analysis, treatment, estrogendependent, signaling, models, androgen, growth, access, mammary, clin, brown,
Topics {✒️}
month download article/chapter multiple cancer/testis antigens hormone-responsive breast cancer cancer/testis antigens tumor-unique er programs high-grade breast cancers cell-specific transcriptional outcomes long-term tamoxifen therapy paracrine fgf/tbx3 signaling common estrogen-regulated genes colorado cancer center breast tumor xenografts asselin-labat ml estrogen-regulated genes expressed high-dose progestin therapy cortisol/mpa serum profiles endocrine-resistant breast cancer hormone-receptor negative nod/scid/iliirg−/− mice tumor grafts derived estrogen receptor regulation estrogen receptor status cancer/testis antigen 45 androgen receptors frequently related subjects xenografts morphologically resembled luminal breast cancers steroid receptor negative estrogen-dependent transcription full article pdf estrogen receptor signaling metastatic breast cancer human breast cancers lower estrogen-receptor breast cancer cells breast tumor cells regulated gene expression er+ breast cancer cancer stem cells estrogen receptor expression human breast carcinoma creighton cj privacy choices/manage cookies human breast tumors androgen receptor expression harvell dm breast cancer care breast cancer based breast cancer regression breast cancer incidence
Questions {❓}
- O’Brien CS, Howell SJ, Farnie G, Clarke RB (2009) Resistance to endocrine therapy: are breast cancer stem cells the culprits?
- Santen RJ (1996) Long-term tamoxifen therapy: can an antagonist become an agonist?
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Estrogen receptors
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