Breast Cancer Stem Cells Regulated Phenotypic Equilibrium Drives Tamoxifen Resistance

Breast cancers consist of heterogeneous cellular subpopulations that differ in molecular properties and functional attributes. Cancer cells display phenotypic equilibrium between the stem-like and differentiated states during neoplastic homeostasis. The mechanism and functional implications of the subpopulation equilibrium in cancer progression remain largely unknown. Herein, we report that BCSCs secretome conditioned bulk tumor cells developed resistance to anti-endocrine therapy both in vitro and in vivo. IL8 was significantly enriched in BCSCs secretome and blockade of IL8 signaling reversed the tamoxifen resistance induced by BCSCs. The enhanced Wnt/ß-catenin signal simultaneously increased the secretion of IL8 in BCSCs, which leads to the seemingly contradictory behaviors of bulk tumor cells. Collectively, our study characterizes the paracrine effects and identifies key molecules secreted by BCSCs, which may become therapeutic vulnerabilities to overcome tamoxifen resistance. Overall design: The BCSCs isolated from flow cytometry sorting or mammospheres culturing were seeded with the regular medium in monolayer culture for 48 hours. The medium from parallelly cultured parental cells was used as the control medium. The conditioned medium was centrifuged at 4,000 g for 3 minutes and filtered with a 0.22 µm filter unit (Millipore) to deplete any cell debris.the BCSCs isolated from flow cytometry sorting or mammospheres culturing were seeded with the regular medium in monolayer culture for 48 hours. The medium from parallelly cultured parental cells was used as the control medium. The conditioned medium was centrifuged at 4,000 g for 3 minutes and filtered with a 0.22 µm filter unit (Millipore) to deplete any cell debris. The MCF-7 cells were cultured with the CM derived from BCSCs or parental cells for 48 hours, and the RNA was isolated and sequenced.