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Integrative analysis of deep sequencing data identifies estrogen receptor early response genes and links ATAD3B to poor survival in breast cancer.

ABSTRACT: Identification of responsive genes to an extra-cellular cue enables characterization of pathophysiologically crucial biological processes. Deep sequencing technologies provide a powerful means to identify responsive genes, which creates a need for computational methods able to analyze dynamic and multi-level deep sequencing data. To answer this need we introduce here a data-driven algorithm, SPINLONG, which is designed to search for genes that match the user-defined hypotheses or models. SPINLONG is applicable to various experimental setups measuring several molecular markers in parallel. To demonstrate the SPINLONG approach, we analyzed ChIP-seq data reporting PolII, estrogen receptor ? (ER?), H3K4me3 and H2A.Z occupancy at five time points in the MCF-7 breast cancer cell line after estradiol stimulus. We obtained 777 ERa early responsive genes and compared the biological functions of the genes having ER? binding within 20 kb of the transcription start site (TSS) to genes without such binding site. Our results show that the non-genomic action of ER? via the MAPK pathway, instead of direct ERa binding, may be responsible for early cell responses to ER? activation. Our results also indicate that the ER? responsive genes triggered by the genomic pathway are transcribed faster than those without ER? binding sites. The survival analysis of the 777 ER? responsive genes with 150 primary breast cancer tumors and in two independent validation cohorts indicated the ATAD3B gene, which does not have ER? binding site within 20 kb of its TSS, to be significantly associated with poor patient survival.

SUBMITTER: Ovaska K

PROVIDER: S-EPMC3688481 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Integrative analysis of deep sequencing data identifies estrogen receptor early response genes and links ATAD3B to poor survival in breast cancer.

Ovaska Kristian K Matarese Filomena F Grote Korbinian K Charapitsa Iryna I Cervera Alejandra A Liu Chengyu C Reid George G Seifert Martin M Stunnenberg Hendrik G HG Hautaniemi Sampsa S

PLoS computational biology 20130620 6

Identification of responsive genes to an extra-cellular cue enables characterization of pathophysiologically crucial biological processes. Deep sequencing technologies provide a powerful means to identify responsive genes, which creates a need for computational methods able to analyze dynamic and multi-level deep sequencing data. To answer this need we introduce here a data-driven algorithm, SPINLONG, which is designed to search for genes that match the user-defined hypotheses or models. SPINLON ...[more]

PMID: 23818839

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Project description:In response to cell stress, cancer cells often activate the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR). Little was known about the potential role in cancer of a different mode of UPR activation, anticipatory activation of the UPR prior to accumulation of unfolded protein or cell stress. We show that estrogen, acting via estrogen receptor ? (ER?), induces rapid anticipatory activation of the UPR, resulting in increased production of the antiapoptotic chaperone BiP/GRP78, preparing cancer cells for the increased protein production required for subsequent estrogen-ER?-induced cell proliferation. In ER?-containing cancer cells, the estrogen, 17?-estradiol (E2) activates the UPR through a phospholipase C ? (PLC?)-mediated opening of EnR IP3R calcium channels, enabling passage of calcium from the lumen of the EnR into the cytosol. siRNA knockdown of ER? blocked the estrogen-mediated increase in cytosol calcium and UPR activation. Knockdown or inhibition of PLC?, or of IP3R, strongly inhibited the estrogen-mediated increases in cytosol calcium, UPR activation and cell proliferation. E2-ER? activates all three arms of the UPR in breast and ovarian cancer cells in culture and in a mouse xenograft. Knockdown of ATF6?, which regulates UPR chaperones, blocked estrogen induction of BiP and strongly inhibited E2-ER?-stimulated cell proliferation. Mild and transient UPR activation by estrogen promotes an adaptive UPR response that protects cells against subsequent UPR-mediated apoptosis. Analysis of data from ER?(+) breast cancers demonstrates elevated expression of a UPR gene signature that is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen therapy, reduced time to recurrence and poor survival. Thus, as an early component of the E2-ER? proliferation program, the mitogen estrogen, drives rapid anticipatory activation of the UPR. Anticipatory activation of the UPR is a new role for estrogens in cancer cell proliferation and resistance to therapy.

Dataset Information

Integrative analysis of deep sequencing data identifies estrogen receptor early response genes and links ATAD3B to poor survival in breast cancer.

Publications

Integrative analysis of deep sequencing data identifies estrogen receptor early response genes and links ATAD3B to poor survival in breast cancer.

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