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Optimizing endocrine therapy for estrogen receptor-positive breast cancer: Treating the right patients for the right length of time

Journal of Clinical Oncology (Impact Factor: 17.88). 05/2008; 26(12):1919-21. DOI: 10.1200/JCO.2007.14.7744
Source: PubMed
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    ABSTRACT: Estrogen signaling plays a critical role in the pathogenesis of breast cancer. Because the majority of breast carcinomas express the estrogen receptor ERα, endocrine therapy that impedes estrogen-ER signaling reduces breast cancer mortality and has become a mainstay of breast cancer treatment. However, patients remain at continued risk of relapse for many years after endocrine treatment. It has been proposed that cancer recurrence may be attributed to cancer stem cells (CSCs)/tumor-initiating cells (TICs). Previous studies in breast cancer have shown that such cells can be enriched and propagated in vitro by culturing the cells in suspension as mammospheres/tumorspheres. Here we established tumorspheres from ERα-positive human breast cancer cell line MCF7 and investigated their response to antiestrogens Tamoxifen and Fulvestrant. The tumorsphere cells express lower levels of ERα and are more tumorigenic in xenograft assays than the parental cells. Both 4-hydroxytamoxifen (4-OHT) and Fulvestrant attenuate tumorsphere cell proliferation, but only 4-OHT at high concentrations interferes with sphere formation. However, treated tumorsphere cells retain the self-renewal capacity. Upon withdrawal of antiestrogens, the treated cells resume tumorsphere formation and their tumorigenic potential remains undamaged. Depletion of ERα shows that ERα is dispensable for tumorsphere formation and xenograft tumor growth in mice. Surprisingly, ERα-depleted tumorspheres display heightened sensitivity to 4-OHT and their sphere-forming capacity is diminished after the drug is removed. These results imply that 4-OHT may inhibit cellular targets besides ERα that are essential for tumorsphere growth, and provide a potential strategy to sensitize tumorspheres to endocrine treatment.
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    ABSTRACT: While the preponderance of current scientific presentations on breast cancer therapies has focused on chemotherapeutic strategies, targeted therapy with tyrosine kinase inhibitors and hormonal therapies for postmenopausal women, the majority of worldwide cases of breast cancer occur in premenopausal women, for whom practical inexpensive hormonal therapy, surgical oophorectomy, is the most common attainable treatment. In hormone-receptor-positive breast cancer, meta-analysis data from older trials, and more specific recent trial data have made clearer the chronic natural history of this broad subtype of disease and the central role of hormonal therapy in its control. Greater understanding of the critical variables in pathology procedures for breast tumor tissue hormonal receptor testing is leading to better definitions of the specific patients for whom hormonal therapies are indicated. Closer examination of outcomes following surgical oophorectomy has suggested that more than just downregulation of estrogen stimulated breast cancer growth; the reduction of systemic estrogen levels also occurs with this procedure. When combined with antiestrogen treatment using tamoxifen in patients who are active metabolizers of this drug, surgical oophorectomy is a remarkably effective and cost-effective treatment. This combination of circumstances suggests that this first hormonal therapy for breast cancer may once again, have a much greater role globally.
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    ABSTRACT: IntroductionRecurrence or early metastasis remains the predominant cause of mortality in patients with estrogen receptor positive (ER+) mammary carcinoma (MC). However, the molecular mechanisms underlying the initial progression of ER¿+¿MC to metastasis remains poorly understood. Trefoil factor 3 (TFF3) is an estrogen-responsive oncogene in MC. Herein, we provide evidence for a functional role of TFF3 in metastatic progression of ER¿+¿MC.Methods The association of TFF3 expression with clinicopathological parameters and survival outcome in a cohort of MC patients was assessed by immunohistochemistry. The expression of TFF3 in MCF7 and T47D cells was modulated by forced expression or siRNA-mediated depletion of TFF3. mRNA and protein levels were determined using qPCR and western blot. The functional effect of modulation of TFF3 expression in MC cells was determined in vitro and in vivo. Mechanistic analyses were performed using reporter constructs, modulation of signal transducer and activator of transcription 3 (STAT3) expression, and pharmacological inhibitors against c-SRC and STAT3 activity.ResultsTFF3 protein expression was positively associated with larger tumour size, lymph node metastasis, higher stage, and poor survival outcome. Forced expression of TFF3 in ER¿+¿MC cells stimulated colony scattering, cell adhesion to a Collagen I-coated matrix, colony formation on a Collagen I- or Matrigel-coated matrix, endothelial cell adhesion, and transmigration through an endothelial cell barrier. In vivo, forced expression of TFF3 in MCF7 cells stimulated the formation of metastatic nodules in animal lungs. TFF3 regulation of the mRNA levels of epithelial, mesenchymal, and metastatic-related genes in ER¿+¿MC cells were consistent with the altered cell behaviour. Forced expression of TFF3 in ER¿+¿MC cells stimulated phosphorylation of c-SRC that subsequently increased STAT3 activity, which lead to the downregulation of E-cadherin. siRNA-mediated depletion of TFF3 reduced the invasiveness of ER¿+¿MC cells.ConclusionsTFF3 expression predicts metastasis and poor survival outcome of patients with MC and functionally stimulates cellular invasion and metastasis of ER¿+¿MC cells. Adjuvant functional inhibition of TFF3 may therefore be considered to ameliorate outcome of ER¿+¿MC patients.
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