Breast cancer stem-cells (BCSCs) are tumor-initiating cells expressing classical embryonal genes such as NANOG, SOX2 and NOTCH1, with a capacity to differentiate and form the heterogenous tumor mass in breast cancer. BCSCs are defined by their potential to grow as mammospheres in vitro together with their distinct cell-surface antigenic profile CD44+/CD24-/EpCAMlow as well as ALDH1-expression. It has been suggested that BCSCs are responsible for therapeutical resistance and metastasis.
About 70-80% of diagnosed breast cancers express ERα, which is demonstrated to have a central role in breast cancer progression and considered as a marker for endocrine sensitivity. However, in our research, BCSCs are confirmed to be ERα negative and supposed to be responding to estrogens only through paracrine signaling via stromal cells. We show that BCSCs purified from fresh surgically resected breast cancers express the second estrogen receptor; ERβ. It is also present in normal mammary stem cells (MSCs) isolated from breast reduction specimens. Surprisingly, stimulation of ERβ with a specific agonist expands the population of BCSCs but not MSCs . Knockdown of ERβ causes reduction in the number of mammospheres significantly along with decreased ALDH1 expression. We also find that treatment with tamoxifen is not sufficient to inhibit BCSCs proliferation although a specific ERβ antagonist reduces tumor growth in xenograft experiments as well as inhibits proliferation of primary cancer stem cells. In conclusion, we suggest endogenous ERβ is proliferative in cancer stem cells in vivo and in vitro, thus can be targeted by specific ligands, in turn opening up for a new direction in endocrine stem-cell specific therapy for breast cancer.
Citation Format: Ran Ma, Karthik Muralidharan Govindasamy, Gustaf Rosin, John Gustafsson, Anne Katchy, Linda Lindström, Camilla Hilliges, Lisa Viberg, Lennart Blomqvist, Jan Frisell, Cecilia Williams, Irma Fredriksson, Jonas Bergh, Johan Hartman. Estrogen receptor β is expressed within breast cancer cells with stem cell like capacity and confers endocrine sensitivity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4915. doi:10.1158/1538-7445.AM2013-4915