tumorspheres directly derived from ER-positive clinical tumor samples will be
examined for their sensitivity to antiestrogen treatment. Consistent with our
in vitro observation, recent clinical studies demonstrate the
positive impact of extended endocrine therapy on suppressing late recurrences in
ER-positive breast cancer , . "
[Show abstract][Hide abstract] 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.
PLoS ONE 04/2011; 6(4):e18810. DOI:10.1371/journal.pone.0018810 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endocrine breast cancer treatment relies on estrogen receptor alpha (ERalpha) assessment, which does not predict response in all cases. We investigated whether ESR1 promoter C driven (ESR1_C) gene expression may shed light on endocrine responsiveness. We investigated archived tumor tissues of 211 patients. Transcript levels of ESR1_C and ESR1_exon3 (all transcripts) were quantified by real-time PCR. mRNA stability was assessed in actinomycin D treated MCF-7 cells. ERalpha protein was quantified using transiently transfected breast cancer cells. Low ESR1_C transcript levels were associated with better overall survival (P = 0.017). High levels of ESR1_C transcript were associated with non-favorable response in tamoxifen treated patients (HR = 2.48; CI 95% 1.24-4.99), an effect that was more pronounced in patients with ERalpha/PgR double-positive tumors (HR = 3.41; CI 95% 1.45-8.04). The ESR1_C isoform had a prolonged mRNA half-life and a more relaxed 5'-UTR structure compared to ESR1_A isoform. ESR1_C levels may aid in the discrimination of patients' endocrine responsiveness.
Breast Cancer Research and Treatment 12/2008; 118(2):323-31. DOI:10.1007/s10549-008-0241-9 · 3.94 Impact Factor
[Show abstract][Hide abstract] 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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