Tamoxifen Stimulates the Growth of Cyclin D1–Overexpressing Breast Cancer Cells by Promoting the Activation of Signal Transducer and Activator of Transcription 3

Abstract

De novo or acquired resistance to tamoxifen is a major clinical challenge for the management of estrogen receptor (ER)-positive breast cancers. Although cyclin D1 overexpression is associated with a better outcome for breast cancer patients, its overexpression is also linked to tamoxifen resistance. We previously reported that the beneficial effect of cyclin D1 correlates with its ability to repress the antiapoptotic transcription factor signal transducer and activator of transcription 3 (STAT3). In contrast, molecular pathways linking overexpression of cyclin D1 to tamoxifen resistance have not been established. In the current study, the effect of tamoxifen on the growth of genetically matched high or low cyclin D1-expressing breast cancer cells was characterized and the interactions between cyclin D1, ER, and STAT3 in response to tamoxifen treatment were determined. We show that repression of STAT3 by cyclin D1 inhibits cell growth on Matrigel and in tumors in vivo; however, treatment with tamoxifen abolishes cyclin D1-mediated repression of STAT3 and growth suppression. We show that tamoxifen induces a redistribution of cyclin D1 from STAT3 to the ER, which results in the activation of both STAT3 and the ER. These results offer a molecular mechanism for the dual effect of cyclin D1 overexpression in breast cancer and support the notion that the level of cyclin D1 expression and activated STAT3 are important markers to predict response to tamoxifen treatment. [Cancer Res 2008;68(3):852-60]

NDRG2 Expression Increases Apoptosis Induced by Doxorubicin in Malignant Breast Caner Cells

“…Inhibition of constitutive STAT3 activation in diverse tumor cell lines, by the blocking of tyrosine kinase signaling using small-molecule inhibitors, has been repeatedly associated with growth suppression and induction of cell death (Epling-Burnette et al, 2001;Garcia et al, 2001;Aggarwal et al, 2006). In addition, it has been reported that upregulation of STAT3 phosphorylation in breast cancer cells reduces the efficiency of chemotherapy (Aggarwal et al, 2006;Gariboldi et al, 2007;Ishii et al, 2008), whereas suppression of STAT3 activation increases the proapoptotic effect of doxorubicin (Gariboldi et al, 2007). Accordingly, we assumed here that inhibition of STAT3 activation by NDRG2 in breast cancer cells may promote apoptosis induced by a chemotherapeutic agent, such as doxorubicin.…”

“…Notably, constitutive activation of STAT3 has frequently been observed in breast cancer and malignant breast cancer cell lines. In addition, STAT3 activation in breast cancer cells decreases the efficiency of chemotherapy (Aggarwal et al, 2006;Gariboldi et al, 2007;Ishii et al, 2008), while STAT3 inhibition increases the proapoptotic effect of doxorubicin (Gariboldi et al, 2007). Thus, the identification of upstream genes regulating STAT3 activation is critical for increasing tumor cell sensitivity to anticancer drugs.…”

Cell Cycle Regulatory Proteins in Breast Cancer: Molecular Determinants of Drug Resistance and Targets for Anticancer Therapies

“…Low expression of cyclin D1 expression was, conversely, associated with high risk of cancer recurrence. Thus, overexpression of cyclin D1 was reported to be actually beneficial for breast cancer survival, associated with inverse tumor grade, smaller tumor size, and improved relapse-free and overall survival of breast cancer patients (Ishii et al, 2008). As a mechanism for such counterintuitive function, it has been proposed that cyclin D1 represses the activity of signal transducer and activator of transcription 3 (STAT3) (Ishii et al, 2006).…”

E-cadherin mediates the aggregation of breast cancer cells induced by tamoxifen and epidermal growth factor

“…Estrogen is required for normal proliferation and differentiation of breast epithelial cells and is implicated in the development and progression of breast cancer [4]. The classical mechanism of estrogen action mainly involves two members of the nuclear receptor superfamily, the estrogen receptor (ER) α and ERß [5].…”

“…Of interest, partial antagonists of ERα, such as 4-hydroxytamoxifen (OHT), may display cell-and promoter-specific agonist effects that are thought to be due, at least in part, to AF1 activity and/or to the ability to recruit cofactors [10][11][12]. OHT was the first antiestrogen approved for the clinical management of ER-positive breast cancers and has been recommended as first-line treatment for the past three decades [4]. Despite the beneficial effects of OHT for patients at all stages of ER-positive breast cancer [13], the major obstacle to its use is the development of tamoxifen-resistance which either occurs de novo or in patients showing initial benefits [14].…”