Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response
| Autor: | Danielle Meijer, Lambert C. J. Dorssers, Anieta M. Sieuwerts, Thecla L. A. van Agthoven, Roya Sarwari, Marion E. Meijer-van Gelder, Stefan Sleijfer, John A. Foekens, Ton van Agthoven |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Cancer Research Antineoplastic Agents Hormonal Endocrinology Diabetes and Metabolism PDGFRB Breast Neoplasms Drug resistance PDGFRA Biology Biomarkers Pharmacological Substrate Specificity Mice Endocrinology Breast cancer medicine Animals Guanine Nucleotide Exchange Factors Humans Neoplasm Invasiveness HRAS Genetic Testing Genetic testing Adaptor Proteins Signal Transducing Aged Retrospective Studies Aged 80 and over medicine.diagnostic_test Estrogen Antagonists Middle Aged medicine.disease Gene Expression Regulation Neoplastic Tamoxifen Crk-Associated Substrate Protein Oncology Drug Resistance Neoplasm Immunology Cancer cell Cancer research Disease Progression Female Genetic screen HeLa Cells |
| Zdroj: | Endocrine-related cancer. 17(1) |
| ISSN: | 1479-6821 |
| Popis: | Although endocrine treatment of breast cancer is effective and common practice, in advanced disease the development of resistance is nearly inevitable. To get more insight into individual genes that account for resistance against hormonal agents, we have executed functional genetic screens and subsequently evaluated the clinical relevance of several identified genes with respect to tumor aggressiveness and tamoxifen resistance in estrogen receptor-positive patients. Estrogen-dependent human breast cancer cells were transduced with different retroviral cDNA expression libraries and subjected to selective cultures with various anti-estrogens. From a total of 264 resistant cell clones, 132 different genes were recovered by PCR. By applying stringent selection criteria, we identified 15 breast cancer anti-estrogen resistance (BCAR) genes individually yielding resistance. BCAR genes were recovered with differential frequencies for the diverse culture conditions and anti-estrogen drugs. Analysis of the relation of BCAR genes (EIF1, FBXL10, HRAS, NRG1, PDGFRA, PDGFRB, RAD21, and RAF1) with tamoxifen treatment in patients with advanced disease showed significant association with clinical benefit and progression-free survival for EIF1 and PDGFRA mRNA levels. Furthermore, PDGFRA and HRAS mRNA levels were significantly associated with tumor aggressiveness in lymph node-negative patients who had not received adjuvant systemic therapy. In conclusion, our functional genetic screens showed that BCAR genes differ in their ability to confer resistance towards distinct anti-estrogens. Based on the clinical relevance of several BCAR genes, further studies are warranted to characterize the underlying mechanisms, which may ultimately lead to the development of novel treatments and more individualized management of breast cancer patients. |
| Databáze: | OpenAIRE |
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