Proinflammatory Cytokines Enhance Estrogen-dependent Expression of the Multidrug Transporter Gene ABCG2 through Estrogen Receptor and NFκB Cooperativity at Adjacent Response Elements

Pradhan, Madhumita; Bembinster, Leslie A.; Baumgarten, Sarah C.; Frasor, Jonna

doi:10.1074/jbc.m110.155309

Cited by 85 publications

(66 citation statements)

References 55 publications

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“…However, there are relatively few examples of ER and NF-B working together to increase transcription (1,30,45,53). Recently, we found that these factors can work cooperatively on a number of genes, including PTGES, which codes for prostaglandin E synthase, and ABCG2, which codes for a drug efflux pump (17,43). For these genes, we demonstrated that NF-B may potentiate ER action by stabilizing ER occupancy on DNA at functional EREs.…”

Section: T He Estrogen Receptor (Er) Is Expressed In Approximately 75%mentioning

confidence: 99%

CBP Mediates NF-κB-Dependent Histone Acetylation and Estrogen Receptor Recruitment to an Estrogen Response Element in the BIRC3 Promoter

Pradhan

Baumgarten

Bembinster

et al. 2012

Molecular and Cellular Biology

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Estrogen receptor (ER) and NF-B are transcription factors with profound effects on breast cancer cell proliferation and survival. While many studies demonstrate that ER and NF-B can repress each other, we previously identified a gene signature that is synergistically upregulated by these two factors in more aggressive luminal B breast tumors. Herein, we examine a novel mechanism of cross talk between ER and NF-B that results in the upregulation of the antiapoptotic gene BIRC3 (also known as cIAP2). We demonstrate that NF-B, acting through two response elements, is required for ER recruitment to an adjacent estrogen response element (ERE) in the BIRC3 promoter. This effect is accompanied by a major increase in NF-B-dependent histone acetylation around the ERE. Interestingly, CBP, a histone acetyltransferase previously implicated in repressive interactions between ER and NF-B, plays a permissive role by promoting histone acetylation and ER recruitment, as well as enhanced expression of BIRC3. These findings suggest a new gene regulatory mechanism by which inflammation and NF-B activation can influence ER recruitment to inherently inactive ER binding sites. This fine-tuning mechanism may explain how two factors that generally repress each other's activity may work together on certain genes to promote breast cancer cell survival and tumor progression. T he estrogen receptor (ER) is expressed in approximately 75%of breast cancers, and women with such tumors are generally treated with endocrine therapies, such as tamoxifen or aromatase inhibitors. However, not all ER-positive tumors respond to these therapies. Through gene expression profiling studies, ER-positive tumors have been delineated into two intrinsic subtypes, luminal A and luminal B (48, 49). Women with the luminal A subtype of breast tumors respond well to therapy and have a good prognosis, whereas the outcome is poor for women with the luminal B subtype of tumors, nearly as poor as that seen in the case of ERnegative tumors. Our lab recently identified a gene signature synergistically upregulated by cross talk between ER and NF-B that is highly associated with luminal B but not luminal A-type tumors (16). This signature is enriched for cell survival genes, including the cellular inhibitor of apoptosis gene, cIAP2, which is also known as BIRC3. We have previously shown that BIRC3 is upregulated by estradiol (E2) and the proinflammatory cytokine tumor necrosis factor alpha (TNF-␣) in a number of ER-positive but not ER-negative cell lines. Using chemical inhibitors and a small interfering RNA (siRNA) approach, our lab has further demonstrated that BIRC3 plays an important role in promoting estrogendependent breast cancer cell survival and protecting against TNF-␣-induced cell death (51). Understanding the mechanism by which BIRC3 is upregulated by cross talk between ER and NF-B is therefore of clinical relevance.The ER subtypes, ER␣ and ER␤, are ligand-dependent transcription factors that interact with DNA and control transcription of ER target genes in resp...

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Section: T He Estrogen Receptor (Er) Is Expressed In Approximately 75%mentioning

confidence: 99%

CBP Mediates NF-κB-Dependent Histone Acetylation and Estrogen Receptor Recruitment to an Estrogen Response Element in the BIRC3 Promoter

Pradhan

Baumgarten

Bembinster

et al. 2012

Molecular and Cellular Biology

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“…Reasons of such contradicting data are not known, but may be related to cell-or organspecific regulation (e.g., organ-specific promoters) or whether transcriptional or posttranscriptional regulation plays a predominant role in experimental systems used in these studies or if there are cooperative interactions between hormones and other regulatory factors. Binding of ER has been shown to enhance transcriptional regulation of the ABCG2 gene by cytokines through p65 or NFkB (189).…”

Section: Regulation Of Bcrp Expressionmentioning

confidence: 99%

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

Mao

Unadkat

2014

AAPS J

519

387

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Abstract. The human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. It was so named because it was initially cloned from a multidrugresistant breast cancer cell line where it was found to confer resistance to chemotherapeutic agents such as mitoxantrone and topotecan. Since its discovery in 1998, the substrates of BCRP have been rapidly expanding to include not only therapeutic agents but also physiological substances such as estrone-3-sulfate, 17β-estradiol 17-(β-D-glucuronide) and uric acid. Likewise, at least hundreds of BCRP inhibitors have been identified. Among normal human tissues, BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure. As a result, BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition. We published a highly-accessed review article on BCRP in 2005, and much progress has been made since then. In this review, we provide an update of current knowledge on basic biochemistry and pharmacological functions of BCRP as well as its relevance to drug resistance and drug disposition.

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“…More specific support for a mechanism of inflammation-mediated modulation of ESR1 comes from more recent discoveries implicating inflammatory and leukocyte-derived cytokines (West et al 2012) and factors (Stossi et al 2012a, Vlaicu et al 2013 as extracellular agents that suppress ESR1 (discussed below). Multiple inflammatory cytokines have been implicated in suppression of ESR1 in breast cancer (Table 1) level of particular ER-target gene promoters (Rubio et al 2006, Pradhan et al 2010. Similarly conflicting findings have been reported for IL6, which was shown to induce methylation of the ESR1 promoter in vitro resulting in reduced levels of ER and an increase in basal-like gene expression patterns (D'Anello et al 2010).…”

Section: Mechanisms Of Inflammation-mediated Er Suppressionmentioning

confidence: 87%

Intratumoural inflammation and endocrine resistance in breast cancer

Murray¹,

West²,

Murphy³

et al. 2014

Endocrine-Related Cancer

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It is becoming clear that inflammation-associated mechanisms can affect progression of breast cancer and modulate responses to treatment. Estrogen receptor alpha (ERa (ESR1)) is the principal biomarker and therapeutic target for endocrine therapies in breast cancer. Over 70% of patients are ESR1-positive at diagnosis and are candidates for endocrine therapy. However, ESR1-positive tumours can become resistant to endocrine therapy. Multiple mechanisms of endocrine resistance have been proposed, including suppression of ESR1. This review discusses the relationship between intratumoural inflammation and endocrine resistance with a particular focus on inflammation-mediated suppression of ESR1.

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Proinflammatory Cytokines Enhance Estrogen-dependent Expression of the Multidrug Transporter Gene ABCG2 through Estrogen Receptor and NFκB Cooperativity at Adjacent Response Elements

Cited by 85 publications

References 55 publications

CBP Mediates NF-κB-Dependent Histone Acetylation and Estrogen Receptor Recruitment to an Estrogen Response Element in the BIRC3 Promoter

CBP Mediates NF-κB-Dependent Histone Acetylation and Estrogen Receptor Recruitment to an Estrogen Response Element in the BIRC3 Promoter

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

Intratumoural inflammation and endocrine resistance in breast cancer

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