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Targeting notch signaling and estrogen receptor pathways in human breast cancer stem cells



Targeting notch signaling and estrogen receptor pathways in human breast cancer stem cells



Journal of Clinical Oncology 26(15_Suppl): 22066-22066



NlmCategory="UNASSIGNED">22066 Background: Breast cancer stem cells have been identified as ESA+CD44+CD24-Lin- cells, which may account for disease relapse and metastasis. Deregulation in stem cell self-renewal pathways such as Notch, Wnt and Hedgehog signaling have been implicated in mammary transformation. In humans, high levels of Notch1 are associated with reduced patient survival. Inhibition of Notch signaling has been proposed as a potential strategy in treating breast cancer. Tamoxifen, a modulator of estrogen receptor (ER), is currently used for the treatment of both early and advanced ER+ breast cancer. It is unclear whether ER+ breast cancers originate from ER+ or ER- mammary stem/progenitor cells. Here, we investigate the molecular mechanisms of Notch signaling and ER interaction in breast cancer stem cells, and evaluate Notch inhibition and estrogen antagonist in targeting breast cancer stem cells. CD44+CD24- breast cancer stem cells are isolated by flow cytometry sorting of (1) human breast cancer cell line MDA-MB-231, (2) primary cells from invasive breast cancer lesions and (3) primary cells from benign breast tissues. Real-time PCR is performed to determine the expression of stem cell genes including genes in Notch pathway. IHC is performed to determine the ER and PR status of the cells. Stem like and non-stem like cells are treated with GSI (a Notch inhibitor) and tamoxifen. The effects of the treatments on cell proliferation and apoptosis are determined by BrdU and Tunnel Assays. Previously we have shown that GSI alone effectively induced apoptosis in ER- MDA-MB-231 cells. Tamoxifen alone had substantial killing effects on ER+ MCF7 cells, but enhanced killing in both cell types were observed when treatments were combined. Stem like, non stem-like and unsorted cells were treated with GSI, tamoxifen and combination of GSI and tamoxifen. Proliferation was determined at 24 and 72 hours of treatment by BrdU assay. Stem-like cells exhibited significant sensitivity to GSI killing In addition, an enhanced effect was observed when GSI was combined with tamoxifen, suggesting that chemotherapy that targets both Notch signaling and estrogen receptor pathways in breast cancer stem cells may be an effective strategy in treating breast cancer. No significant financial relationships to disclose.

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Accession: 058974639

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PMID: 27950676


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