Abstract. It is believed that breast cancer stem cells (BCSCs), like normal stem cell counterparts, have the capacity of selfrenewal and differentiation. Simultaneously, estrogen receptor (ER)-negative (-) BCSCs are affected by surrounding differentiated ER-positive (+) tumor cells by virtue of paracrine signaling within the tumor micro environment. Genistein (GEN), as a sort of phytoestrogen, can act on ER + breast cancer cells but the role of GEN in the differentiation of neighboring ER -BCSCs has not been defined. Transwell co-culture system was utilized so as to elaborate the interaction between welldifferentiated ER + breast cancer cells (MCF-7) and ER -breast cancer stem/progenitor cells (mammospheres derived from MDA-MB-231 cells). GEN-induced differentiation of BCSCs was analyzed by mammospheres formation assay, flow cytometry and RT-PCR after a 3 day solo-culture or co-culture. We find that GEN sized 2 µM, and 40 nM, effectively promotes morphological alteration of mammospheres, reduces the ratio of subset of CD44 + /CD24 -/ESA + cells and upregulates the expression of differentiated cell markers of mammospheres in co-culture system, but not in solo-culture condition. Besides, we demonstrate that the differentiation-inducing effect of GEN on mammospheres is associated with PI3K/ Akt and MEK/ERK signaling pathways which are activated by amphiregulin released from ER + cancer cells. These results indicate that GEN was able to induce the differentiation of breast cancer stem/progenitor cells through interaction with ER + cancer cells by a paracrine mechanism.

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