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A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance.

ABSTRACT: PURPOSE:Although most patients with estrogen receptor ? (ER)-positive breast cancer initially respond to endocrine therapy, many ultimately develop resistance to antiestrogens. However, mechanisms of antiestrogen resistance and biomarkers predictive of such resistance are underdeveloped. EXPERIMENTAL DESIGN:We adapted four ER(+) human breast cancer cell lines to grow in an estrogen-depleted medium. A gene signature of estrogen independence was developed by comparing expression profiles of long-term estrogen-deprived (LTED) cells to their parental counterparts. We evaluated the ability of the LTED signature to predict tumor response to neoadjuvant therapy with an aromatase inhibitor and disease outcome following adjuvant tamoxifen. We utilized Gene Set Analysis (GSA) of LTED cell gene expression profiles and a loss-of-function approach to identify pathways causally associated with resistance to endocrine therapy. RESULTS:The LTED gene expression signature was predictive of high tumor cell proliferation following neoadjuvant therapy with anastrozole and letrozole, each in different patient cohorts. This signature was also predictive of poor recurrence-free survival in two studies of patients treated with adjuvant tamoxifen. Bioinformatic interrogation of expression profiles in LTED cells revealed a signature of MYC activation. The MYC activation signature and high MYC protein levels were both predictive of poor outcome following tamoxifen therapy. Finally, knockdown of MYC inhibited LTED cell growth. CONCLUSIONS:A gene expression signature derived from ER(+) breast cancer cells with acquired hormone independence predicted tumor response to aromatase inhibitors and associated with clinical markers of resistance to tamoxifen. Activation of the MYC pathway was associated with this resistance.

SUBMITTER: Miller TW

PROVIDER: S-EPMC3221728 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance.

Miller Todd W TW Balko Justin M JM Ghazoui Zara Z Dunbier Anita A Anderson Helen H Dowsett Mitch M González-Angulo Ana M AM Mills Gordon B GB Miller William R WR Wu Huiyun H Shyr Yu Y Arteaga Carlos L CL

Clinical cancer research : an official journal of the American Association for Cancer Research 20110223 7

<h4>Purpose</h4>Although most patients with estrogen receptor α (ER)-positive breast cancer initially respond to endocrine therapy, many ultimately develop resistance to antiestrogens. However, mechanisms of antiestrogen resistance and biomarkers predictive of such resistance are underdeveloped.<h4>Experimental design</h4>We adapted four ER(+) human breast cancer cell lines to grow in an estrogen-depleted medium. A gene signature of estrogen independence was developed by comparing expression pro ...[more]

PMID: 21346144

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Project description:Human X-box binding protein-1 (XBP1) is an alternatively spliced transcription factor that participates in the unfolded protein response (UPR), a stress signaling pathway that allows cells to survive the accumulation of unfolded proteins in the endoplasmic reticulum lumen. We have previously demonstrated that XBP1 expression is increased in antiestrogen-resistant breast cancer cell lines, and is co-expressed with estrogen receptor alpha (ER) in breast tumors. The purpose of this study is to investigate the role of XBP1 and the UPR in estrogen and antiestrogen responsiveness in breast cancer. Overexpression of spliced XBP1 (XBP1(S)) in ER-positive breast cancer cells leads to estrogen-independent growth and reduced sensitivity to growth inhibition induced by the antiestrogens Tamoxifen and Faslodex in a manner independent of functional p53. Data from gene expression microarray analyses imply that XBP1(S) acts through regulating the expression of ER, the anti-apoptotic gene BCL2, and several other genes associated with control of the cell cycle and apoptosis. Experiment Overall Design: Total RNA was isolated from six independent cultures (cell populations grown on different days from different stocks); three from MCF7/XBP1 cultures and three from the vector control cultures. MIAME 1.1 compliant data were collected as recommended by the Microarray Gene Expression Data (MGED) Society. RNA concentrations were determined by comparing the optical density ratios (260:280 nm) , and data on RNA quality was obtained using an Agilent 2100 Bioanalyzer and RNA 6000 LabChip kits (Agilent Technologies, New Castle, DE). RNA quality was assessed by visual inspection of the electropherograms from the Bioanalyzer data, and by the calculated RNA integrity numbers (RIN) and Degradometer values . Only high quality total RNA was labeled and hybridized to U133A Affymetrix GeneChips using manufacturer recommended procedures (Affymetrix, Santa Clara, CA). Standard “spiked-in” controls also were included in each hybridization.

Dataset Information

A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance.

Publications

A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance.

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