Response of Estrogen Receptor-Positive Breast Cancer Tumorspheres to Antiestrogen Treatments
Open Access
- 14 April 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (4), e18810
- https://doi.org/10.1371/journal.pone.0018810
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.Keywords
This publication has 36 references indexed in Scilit:
- Antiestrogen-resistant subclones of MCF-7 human breast cancer cells are derived from a common monoclonal drug-resistant progenitorProceedings of the National Academy of Sciences of the United States of America, 2009
- Implications of the Cancer Stem-Cell Hypothesis for Breast Cancer Prevention and TherapyJournal of Clinical Oncology, 2008
- Mammosphere culture of metastatic breast cancer cells enriches for tumorigenic breast cancer cellsBreast Cancer Research, 2008
- Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapyBreast Cancer Research, 2008
- Human breast cancer stem cell markers CD44 and CD24: enriching for cells with functional properties in mice or in man?Breast Cancer Research, 2007
- Evidence for a stem cell hierarchy in the adult human breastThe Journal of cell biology, 2007
- Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary glandThe Journal of cell biology, 2006
- Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trialsThe Lancet, 2005
- Prospective identification of tumorigenic breast cancer cellsProceedings of the National Academy of Sciences, 2003
- Gene expression profiling predicts clinical outcome of breast cancerNature, 2002