title: Genistein-induced differentiation of breast cancer stem/progenitor cells through a paracrine mechanism.
abstract: It is believed that breast cancer stem cells (BCSCs), like normal stem cell counterparts, have the capacity of self-renewal 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 well-differentiated 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.
authors.affiliation: The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China.
authors.forename: Yanchen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The Fifth Hospital of Harbin City, Harbin, Heilongjiang, P.R. China.
authors.forename: Tianbiao
authors.initials: T
authors.lastname: Zou
authors.affiliation: The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China.
authors.forename: Shuhuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China.
authors.forename: Dongju
authors.initials: D
authors.lastname: Su
authors.affiliation: The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Fu
authors.affiliation: The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China.
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China.
authors.forename: Xinmei
authors.initials: X
authors.lastname: Kang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000737:chemistry; D004958:Estradiol / Q000737:chemistry; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D019833:Genistein / Q000737:chemistry*; D006801:Humans; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000166:cytology*; D019899:Paracrine Communication; D048789:Phytoestrogens / Q000737:chemistry; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D048789:Phytoestrogens; D004958:Estradiol; D019833:Genistein