In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1748-1748
Abstract:
Background: Triple negative breast cancers (TNBC) account for approximately 15% of breast cancer but 30% of deaths. The majority of TNBC are basal breast cancers that have higher rate of relapses as compared with other breast cancer subtypes, indicating there exists a sub-population of tumor cells that are highly resistant to chemotherapies. Platinum-based agents and PARP inhibitors have shown efficacy in basal breast cancers with BRCA1/2 mutation background. In this study, we expand the analysis to basal breast cancer lines without BRCA1/2 mutations. Results and Methods: We treated a panel of basal breast cancer lines (HCC70, MDA-MB-468, BT549, HCC1143) with cisplatin and observed that 6 µM of cisplatin were able to kill & gt;99% of a confluent plate of these cell lines. The cisplatin-resistant population, however, behaved very differently in these lines. Cisplatin-resistant MDA-MB-468 cells had similar phenotype as cisplatin-sensitive cells and they repopulated the whole plate in a short time. Cisplatin-resistant cells in the other 3 TNBC lines had a different phenotype than the cisplatin-sensitive cells and remained quiescent for 2-3 weeks before proliferating in a vertical fashion. The vertical string of cells eventually detached from the plate and kept expanding as clusters of cells in suspension. Screening through various drugs, we observed that 2 mM of metformin as a combined treatment with cisplatin was able to irradicate these cisplatin-resistant cells in both MDA-MB-468 and BT549 cell lines. Additionally, we demonstrated that using aminoimidazole carboxamide ribonucleotide (AICAR), an AMP kinase (AMPK) activator, and Rapamycin, an mTORC1 inhibitor had the same effect as metformin indicating the AMPK-mTOR axis might be important for the survival of cisplatin-resistant cells. Conclusions: TNBC without BRCA1/2 mutation are sensitive to cisplatin treatment but possess a sub-population of resistant cells. We demonstrated that cisplatin-resistant cells in TNBC lines behaved differently after cisplatin treatment and that combined treatment of metformin and cisplatin may be able to overcome this resistance. Future experiments include comparing this combination with the combined treatment of cisplatin and PARP inhibitor, which might have effect in cisplatin-sensitive cells but not in cisplatin-resistant cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1748. doi:10.1158/1538-7445.AM2011-1748
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-1748
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Permalink