Abstract 2024: BP1 homeoprotein induces tumor cell growth and estrogen-independent tumorigenesis in mice
| Autor: | Arnold M. Schwartz, Erika Ginsburg, Saurabh Kirolikar, Sidney W. Fu, Patricia E. Berg, Samuel J. Simmens |
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| Rok vydání: | 2016 |
| Předmět: |
Cancer Research
medicine.drug_class Chemistry fungi Transfection medicine.disease medicine.disease_cause environment and public health Metastasis enzymes and coenzymes (carbohydrates) Oncology Downregulation and upregulation Estrogen medicine Cancer research biological phenomena cell phenomena and immunity Carcinogenesis Transcription factor Estrogen receptor alpha Tamoxifen medicine.drug |
| Zdroj: | Cancer Research. 76:2024-2024 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | BACKGROUND. BP1 is a member of the homeobox gene family of transcription factors. Our recent studies have shown that BP1 overexpression increases cell survival, aggressiveness and metastasis in breast cancer cells. BP1 protein is expressed in 80% of invasive ductal breast tumors, including 100% of ER negative (ER-) tumors and 73% of ER positive (ER+) tumors. Therefore we hypothesize that BP1 may regulate ER in breast cancer. A mouse model was developed to test the regulatory effects of BP1 in ER expression. MATERIALS AND METHODS. MCF-7 breast cancer cells transfected with BP1 or vector control were njected into the fat pads of nude mice. Regulation of ER by BP1 was studied using ChIP assays; EMSA assays were used to test binding of BP1 to ER DNA. Tamoxifen assays were used to evaluate the effects of BP1 overexpression on tamoxifen resistance. RESULTS. MCF-7 cells overexpressing BP1 or control cells containing an empty vector were injected into nude mice. Approximately half of the estrogen-supplemented mice developed tumors. Although MCF-7 cells require exogenous estrogen to form tumors in nude mice, approximately 20% of the mice implanted with cells overexpressing BP1 were able to form tumors in the absence of added estrogen. To understand the molecular mechanisms of this observation, we carried out in vitro experiments. Our data suggest that BP1 regulates ER both directly and indirectly: (1) Direct: ChIP assays and EMSA assays showed that BP1 binds to the first intron of the ER alpha gene and transcriptionally activates it, leading to increased ER protein. (2) Indirect: regulation of ER also occurs indirectly by BP1 upregulation of p300, an activator of ER, and also by repression of BRCA1 by BP1; BRCA1 destabilizes ER protein. Furthermore, MCF-7 cells overexpressing BP1 are more resistant to growth in 3uM tamoxifen compared with empty vector containing cells. CONCLUSIONS. BP1 overexpression in MCF-7 cells injected into mice not only increases tumor size but also promotes estrogen-independent tumorigenesis, and leads to resistance to tamoxifen. Therefore, BP1 could serve as a novel therapeutic target for ER+ breast cancer. Citation Format: Sidney W. Fu, Saurabh Kirolikar, Erika Ginsburg, Arnold Schwartz, Samuel Simmens, Patricia E. Berg. BP1 homeoprotein induces tumor cell growth and estrogen-independent tumorigenesis in mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2024. |
| Databáze: | OpenAIRE |
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