Abstract
IntroductionAlthough oestrogen is essential for the development of the normal breast, adult mammary stem cells are known to be oestrogen receptor alpha (ER) negative and rely on paracrine signals in the mammary epithelium for mediation of developmental cues. However, little is known about how systemic oestrogen regulates breast cancer stem cell (CSC) activity.MethodsHere, we tested the effects of oestrogen on CSC activity in vitro and in vivo and investigated which paracrine signalling pathways locally mediate oestrogen effects.ResultsCSC-enriched populations (ESA+CD44+CD24low) sorted from ER positive patient derived and established cell lines have low or absent ER expression. However, oestrogen stimulated CSC activity demonstrated by increased mammosphere and holoclone formation in vitro and tumour formation in vivo. This effect was abrogated by the anti-oestrogen tamoxifen or ER siRNA. These data suggest that the oestrogen response is mediated through paracrine signalling from non-CSCs to CSCs. We have, therefore, investigated both epidermal growth factor (EGF) and Notch receptor signals downstream of oestrogen. We demonstrate that gefitinib (epidermal growth factor receptor (EGFR) inhibitor) and gamma secretase inhibitors (Notch inhibitor) block oestrogen-induced CSC activity in vitro and in vivo but GSIs more efficiently reduce CSC frequency.ConclusionsThese data establish that EGF and Notch receptor signalling pathways operate downstream of oestrogen in the regulation of ER negative CSCs.
Highlights
Oestrogen is essential for the development of the normal breast, adult mammary stem cells are known to be oestrogen receptor alpha (ER) negative and rely on paracrine signals in the mammary epithelium for mediation of developmental cues
Oestrogen stimulation increases the breast cancer stem cell-like population The effect of 17b-estradiol on the CSC proportion was assessed in three ER positive patient derived cell samples, three ER positive cell lines (MCF7, T47D and BT474) and an ER negative cell line (MDA-MB-231)
Following oestrogen deprivation for six days and 48 hours culture in 1 nM 17b-estradiol, the mammosphere forming cell (MFC) number was significantly increased in all ER positive but not ER negative primary cells and cell lines (Figure 1A)
Summary
Oestrogen is essential for the development of the normal breast, adult mammary stem cells are known to be oestrogen receptor alpha (ER) negative and rely on paracrine signals in the mammary epithelium for mediation of developmental cues. Little is known about how systemic oestrogen regulates breast cancer stem cell (CSC) activity. Normal mammary stem cells (MSC) are responsible for the generation of adult mammary tissue and the distinct cell types within it as well as the extensive remodelling and enlargement of the gland during multiple cycles of pregnancy [1,2]. The development and progression of breast tumours has been proposed to be driven by breast cancer stem cells (CSC) identified by the cell surface phenotype ESA +CD44+CD24low or aldehyde dehydrogenase (ALDH1) activity [7,8]. CSCs are thought to be responsible for tumour recurrence as they have been shown to be inherently resistant to therapies, such as chemotherapy [9], radiotherapy [10] and endocrine treatment [11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
