Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor

Wang, Li Hua; Yang, Xiao Yi; Zhang, Xiaohu; Mihalic, Kelly; Fan, Yi; Xiao, Wu; Howard, O. M. Zack; Appella, Ettore; Maynard, Andy; Farrar, William L.

doi:10.1038/nm969

Cited by 75 publications

(88 citation statements)

References 37 publications

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“…Studies have shown that prevention of ER binding to ERE sequences of responsive genes by exogenously introduced ERE decoys (21) or electrophilic agents that disrupt zinc-fingers of ERα (22)(23)(24) represses E2-mediated growth of ERpositive breast cancer cells. Complementing this, we recently reported that genomic responses from the ERE-dependent pathway mediated by E2-ER are required to suppress the growth of ER-negative cells as well (10,11).…”

Section: Discussionmentioning

confidence: 99%

Designer Monotransregulators Provide a Basis for a Transcriptional Therapy for De Novo Endocrine-Resistant Breast Cancer

Nott

Huang

Kalkanoglu

et al. 2009

Mol Med

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The main circulating estrogen hormone 17β-estradiol (E2) contributes to the initiation and progression of breast cancer. Estrogen receptors (ERs), as transcription factors, mediate the effects of E2. Ablation of the circulating E2 and/or prevention of ER functions constitute approaches for ER-positive breast cancer treatments. These modalities are, however, ineffective in de novo endocrine-resistant breast neoplasms that do not express ERs. The interaction of E2-ERs with specific DNA sequences, estrogen responsive elements (EREs), of genes constitutes one genomic pathway necessary for cellular alterations. We herein tested the prediction that specific regulation of ERE-driven genes by an engineered monomeric and constitutively active transcription factor, monotransregulator, provides a basis for the treatment of ER-negative breast cancer. Using adenovirus infected ER-negative MDA-MB-231 cells derived from a breast adenocarcinoma, we found that the monotransregulator, but not the ERE-binding defective counterpart, repressed cellular proliferation and motility, and induced apoptosis through expression of genes that required ERE interactions. Similarly, the monotransregulator suppressed the growth of ER-negative BT-549 cells derived from a breast-ductal carcinoma. Moreover, the ERE-binding monotransregulator repressed xenograft tumor growth in a nude mice model. Thus, specific regulation of genes bearing EREs could offer a therapeutic approach for de novo endocrine-resistant breast cancers.

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Section: Discussionmentioning

confidence: 99%

Designer Monotransregulators Provide a Basis for a Transcriptional Therapy for De Novo Endocrine-Resistant Breast Cancer

Nott

Huang

Kalkanoglu

et al. 2009

Mol Med

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“…1,2 In medicine, benzisothiazole derivatives act as antibiotic agents, 3 as phospholipase inhibitors in the treatment of hepatic diseases, 4 as inhibitors of the human leukocyte elastase, 5,6 and as selective blockers of the estrogen receptor, in the treatment of breast cancer. 7 A new class of substituted benzisothiazolones has shown antiviral activity against retroviruses (e.g., HIV virus), 8 and the first nonbenzoannelated 4-amino-2,3-dihydroisothiazole 1,1-dioxide, lacking a 3-oxo group, has recently been described and shows anti-HIV-1 activity. 9,10 Pseudosaccharyl ethers have particularly important synthetic uses as intermediate compounds for reductive cleavage of the C-O bond in phenols and alcohols.…”

Section: Introductionmentioning

confidence: 99%

Thermally Induced Sigmatropic Isomerization of Pseudosaccharyl Allylic Ether

et al. 2009

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The thermally induced sigmatropic isomerization of the pseudosaccharyl allylic ether [3-(allyloxy)-1,2-benzisothiazole 1,1-dioxide; ABID] has been investigated by a multidisciplinary approach using temperature dependent infrared spectroscopy, differential scanning calorimetry, and polarized light thermomicroscopy, complemented by theoretical methods. Migration of the allylic system from O to N occurs in the melted ABID, and the thermally obtained 2-allyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (ABIOD) starts to be produced at ca. 150 °C, in a process with an activation energy of ∼92 kJ mol−1. From kinetic data, a concerted [3,3′] sigmatropic mechanism is proposed. In the temperature range investigated, ABIOD was found to exhibit polymorphism. Cooling of the molten compound leads to the production of a metastable crystalline form, which upon annealing at room temperature might be transformed to the stable crystalline phase. ABID shows a single crystalline variety. Assignments were proposed for the infrared spectra of the observed neat condensed phases of the two compounds.

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“…In addition, it has also been shown that some benzisothiazolone derivatives selectively block binding of the estrogen receptor in breast cancer. Therefore, these compounds are being currently used in antiestrogen therapy for breast cancer [9]. More recently, a new class of substituted 2-benzisothiazolones has been proven to exhibit antiviral activity against retroviruses (e.g., HIV virus) [10].…”

Section: Introductionmentioning

confidence: 99%

Conformational and structural analysis of 2-allyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide as probed by matrix-isolation spectroscopy and quantum chemical calculations

Gómez‐Zavaglia

Kaczor

Coelho

et al. 2009

Journal of Molecular Structure

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a b s t r a c t 2-Allyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (ABIOD) has been studied by matrix-isolation infrared spectroscopy and quantum chemical calculations. A conformational search on the B3LYP/6-311++G(3df,3pd) potential energy surface of the molecule demonstrated the existence of three conformers, Sk, Sk 0 and C, with similar energies, differing in the orientation of the allyl group. The calculations predicted the Sk form as the most stable in the gaseous phase, whereas the Sk 0 and C conformers have calculated relative energies of ca. 0.6 and 0.8-3.0 kJ mol À1 , respectively (depending on the level of theory). In agreement with the relatively large (>6 kJ mol À1 ) calculated barriers for conformational interconversion, the three conformers could be efficiently trapped in an argon matrix at 10 K, the experimental infrared spectrum of the as-deposited matrix fitting well the simulated spectrum built from the calculated spectra for individual conformers scaled by their predicted populations at the temperature of the vapour of the compound prior to matrix deposition. Upon annealing the matrix at 24 K, however, both Sk and Sk 0 conformers were found to convert to the more polar C conformer, indicating that this latter form becomes the most stable ABIOD conformer in the argon matrix.

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Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor

Cited by 75 publications

References 37 publications

Designer Monotransregulators Provide a Basis for a Transcriptional Therapy for De Novo Endocrine-Resistant Breast Cancer

Designer Monotransregulators Provide a Basis for a Transcriptional Therapy for De Novo Endocrine-Resistant Breast Cancer

Thermally Induced Sigmatropic Isomerization of Pseudosaccharyl Allylic Ether

Conformational and structural analysis of 2-allyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide as probed by matrix-isolation spectroscopy and quantum chemical calculations

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