Inhibition of human breast cancer colony formation by anticalmodulin agents: Trifluoperazine, W-7, and W-13

Wei, Jiann-Wu; Hickie, Robert A.; Klaassen, David J.

doi:10.1007/bf00254251

Cited by 66 publications

(26 citation statements)

References 15 publications

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“…Regardless of the mechanism, our data contribute to deciphering the intricate meshwork of ER signaling pathways. In addition, they further explain the prior observations that calmodulin antagonists inhibit the growth of breast cell lines (29) and synergistically amplify antiestrogen therapy (30).…”

Section: Development Of Cambps To Specifically Inhibit Calmodulin In supporting

confidence: 62%

Calmodulin Regulates the Transcriptional Activity of Estrogen Receptors

Sacks

2003

Journal of Biological Chemistry

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The steroid hormone estrogen elicits biological effects in cells by binding to and activating the estrogen receptor (ER). Estrogen binding induces a conformational change in the receptor, inducing nuclear translocation and transcriptional activation of ER. The ubiquitous Ca 2؉ -binding protein calmodulin has been shown to interact directly with ER and enhance its stability. To further elucidate the functional sequelae of the association between calmodulin and ER, we examined the effect on ER transcriptional activation of specifically inhibiting calmodulin. The cell-permeable calmodulin antagonist CGS9343B prevented estrogen-induced transcriptional activation by ER, without altering basal transcription. The inhibition was dose-dependent and independent of the time of estrogen stimulation. To validate these findings, calmodulin function was also neutralized by targeted expression of a specific inhibitor peptide. By inserting localization signals, the inhibitor peptide was selectively targeted to different subcellular domains. Inactivation of calmodulin function in the nucleus virtually eliminated estrogen-stimulated ER transcriptional activation. By contrast, when membrane calmodulin was specifically neutralized, estrogen-stimulated transcriptional activation by ER was only slightly attenuated. Importantly, the inhibitor peptides did not significantly reduce the amount of ER in the cells. Together, these data demonstrate that calmodulin is a fundamental component of ER transcriptional activation.The classic steroid hormone estrogen promotes the proliferation of both normal and malignant breast epithelial cells and shortens the cell cycle. Estrogen mediates its biological effects in cells through the estrogen receptor (ER), 1 a member of the nuclear receptor family of ligand-dependent transcription factors (reviewed in Refs. 1 and 2). Analogous to other steroid hormone receptors, ER is an intracellular transcription factor composed of six domains. Estrogen binding to the C-terminal hormone-binding domain induces conformational changes in ER, thereby promoting its dimerization and nuclear localization. The DNA-binding domain of the activated ER binds to DNA sequences, termed estrogen response elements, found in the regulatory regions of target genes. Several factors, including coactivators, corepressors, and integrator proteins, are important in ER-mediated transcription (reviewed in Refs. 3 and 4). It is becoming apparent that transcriptional regulation requires the recruitment by ER of multiple, distinct proteins that cooperate to achieve the required response (3). These factors can alter the magnitude of cellular responses to estrogen.There are yet additional factors that modulate ER function. For example, ER interacts with members of the heat-shock protein family (1), and dissociation of heat-shock protein seems to be necessary for ER to activate transcription. One of the major roles of ligand binding is to change the nature of proteinprotein interactions between steroid receptors and other proteins (2). Convers...

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Section: Development Of Cambps To Specifically Inhibit Calmodulin In supporting

confidence: 62%

Calmodulin Regulates the Transcriptional Activity of Estrogen Receptors

Sacks

2003

Journal of Biological Chemistry

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“…Regardless of the mechanism, our data contribute to deciphering the intricate meshwork of ER signaling pathways. In addition, they further explain the prior observations that calmodulin antagonists inhibit the growth of breast cell hnes (29) and synergistically amplify antiestrogen therapy (30).…”

Section: Development Of Cambps To Specifically Inhibit Calmodulin In supporting

confidence: 61%

The Role of Ca2+ and Calmodulin in Estrogen Receptor Function and Tamoxifen Resistance

Sacks¹

2003

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SUPPLEMENTARY NOTESOriginal contains color plates: All DTIC reproductions will be in black and white. The purpose of this proposal is to evaluate the participation of Ca^* and calmodulin in estrogen receptor (ER) function and tamoxifen resistance. The focus is directed towards the interaction between calmodulin and ER in ER signaling, as well as the possible involvement of Ca^'' and calmodulin in tamoxifen resistance. Major findings to date are: (i) calmodulin binds directly to ER and stabilizes the receptor; (ii) calmodulin protects ER from degradation in the proteasome pathway; (iii) calmodulin is necessary for estrogenstimulated transcriptional activation by ER; (iv) the effect of calmodulin in ER transcriptional activation is independent of its effect on ER stability; and (v) inhibition of calmodulin function in the nucleus, but not at the plasma membrane, eliminates estrogen-induced transcriptional activation by ER. These data reveal that calmodulin is a component of both ER stability and ER transcriptional activity. This information could have potential therapeutic implications in patients with breast cancer.

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“…This postulate may also explain why CaM antagonists impede the growth of breast cancer cells and synergistically augment the antiproliferative action of antiestrogens (Strobl et a l., 1994;Wei et al, 1983). …”

Section: Discussionmentioning

confidence: 99%