+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

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.

(PDF emailed within 1 workday: $29.90)

Accession: 058974639

Download citation: RISBibTeXText

PMID: 27950676

Related references

Targeting Notch signaling cross-talk with estrogen receptor and ErbB-2 in breast cancer. Advances in Enzyme Regulation 49(1): 134-141, 2009

Targeting up-regulated notch signaling in the CD133+stem cells within breast cancer. 2007

MiR-129 blocks estrogen induction of NOTCH signaling activity in breast cancer stem-like cells. Oncotarget 8(61): 103261-103273, 2017

Improved antitumor therapy by dual targeting of estrogen and growth factor receptor signaling in human breast cancer cells. Journal of Clinical Oncology 24(18_Suppl): 637-637, 2016

Targeting Cellular Signaling Pathways in Breast Cancer Stem Cells and its Implication for Cancer Treatment. Anticancer Research 36(11): 5681-5691, 2016

Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. Seminars in Cancer Biology 40-41: 192-208, 2016

Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling. Oncotarget 6(41): 43375-43394, 2016

Breast cancer cells can switch between estrogen receptor alpha and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance. Breast Cancer Research and Treatment 121(3): 601-613, 2011

Improved antitumor therapy with Herceptin and Faslodex for dual targeting of HER-2 and estrogen receptor signaling pathways in human breast cancers with overexpression of HER-2/neu gene. Breast Cancer Research & Treatment 82(Suppl. 1): S12-S13, 2003

Melatonin inhibits the proliferation of breast cancer cells induced by bisphenol A via targeting estrogen receptor-related pathways. Thoracic Cancer 9(3): 368-375, 2018

Abnormal expression of the Notch and Wnt/β-catenin signaling pathways in stem-like ALDH hi CD44 + cells correlates highly with Ki-67 expression in breast cancer. Oncology Letters 9(4): 1600-1606, 2015

MiR-206 suppresses epithelial mesenchymal transition by targeting TGF-β signaling in estrogen receptor positive breast cancer cells. Oncotarget 7(17): 24537-24548, 2017

Bidirectional Crosstalk between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 Signaling Pathways in Breast Cancer: Molecular Basis and Clinical Implications. Breast Care 8(4): 256-262, 2014

The phenomenon of acquired resistance to metformin in breast cancer cells: The interaction of growth pathways and estrogen receptor signaling. Iubmb Life 68(4): 281-292, 2016

Effects of cadmium on estrogen receptor mediated signaling and estrogen induced DNA synthesis in T47D human breast cancer cells. Toxicology Letters 184(2): 134-138, 2008