In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2572-2572
Abstract:
Triple negative breast cancer (TNBC) is clinically characterized as an aggressive form of cancer which is unresponsive to hormone and trastuzumab based therapies and associated with poorer overall patient prognosis. TNBC can be treated with chemotherapeutic agents but unfortunately typically half of patients do not respond to treatment because their breast cancer cells become resistant. Recent evidence suggests that psychological distress in cancer patients equates to poor chemotherapeutic response, indeed the National Cancer Institute reports that 50% of cancer patients report anxiety due to the cancer diagnosis, the fear of dying and chemotherapy. Historically, single markers depicting breast cancer prognosis have failed to readily translate to the clinic therefore the expression pattern of multiple molecules may prove better predictors of drug resistance to chemotherapeutic agents. We hypothesize that drug resistance in breast cancer may arise in part due to stress hormone-induced alterations in intrinsic cellular proteins/genes in cancer cells. To examine the effects of stress, via stress hormones on drug resistance MDA-MB-231 breast cancer cells were incubated with paclitaxel in the presence of physiological concentrations of cortisol, norepinephrine and epinephrine for 48 h. We utilized a quantitative proteomic strategy, Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC), and LC-MS/MS to compare differences in protein abundance between paclitaxel-treated and stress hormone/paclitaxel-treated cells. For proteomic profiling, paclitaxel-treated cells cultured in unlabeled (no stress hormones) and labeled (stress hormones) SILAC media were mixed, lysed, and proteins were resolved by 1D-SDS PAGE, digested in-gel with trypsin and analyzed by LC-MS/MS. For genomic analyses, total RNA was isolated using TRIzol, cRNA was generated and hybridized to Affymetrix GeneChip HGU133 plus 2.0 arrays. We identified 220 proteins and 1201 genes whose expression levels were significantly altered by stress hormones. We further identified a unique molecular profile of predictive candidate biomarkers related to stress hormone- induced drug resistance including a significant decrease in the mitotic checkpoint serine/threonine-protein kinase BUB1 and the DNA damage response enzyme PARP-1, and increases in the immunophillin, FKBP-5 and the cell proliferation/apoptosis regulator C-MYC. In conclusion, our results demonstrate that stress hormones promote resistance to paclitaxel through modulation of several markers of drug resistance in TNBC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2572.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-2572
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
