title: Stromal cells promote anti-estrogen resistance of breast cancer cells through an insulin-like growth factor binding protein 5 (IGFBP5)/B-cell leukemia/lymphoma 3 (Bcl-3) axis.
abstract: There is strong evidence that stromal cells promote drug resistance of cancer. Here, we show that mesenchymal stem cells (MSCs) and carcinoma-associated fibroblasts (CAFs) desensitize ERα-positive breast cancer cells to the anti-estrogen fulvestrant. In search for the mechanism, we found that MSCs and CAFs similarly increased the activity of the PI3K/AKT and the JAK/STAT3 pathways and upregulated the expression of integrin β1, IGF1R, HIF1α, CAIX and Bcl-3 in MCF-7 cells. Further analyses revealed that MSCs and CAFs coordinately induce these changes by triggering the downregulation of IGFBP5. Loss of IGFBP5 in MCF-7 cells was an early and long-lasting event in response to MSCs and CAFs and was accompanied by growth stimulation both in the absence and presence of fulvestrant. The growth-stimulatory effect in the absence of fulvestrant could be attributed to PI3K/AKT pathway activation and could be mimicked by insulin. The growth-promoting effect in the presence of fulvestrant depended upon the upregulation of Bcl-3. By cRNA microarray analysis we identified additional IGFBP5 targets, of which two (KLHL4 and SEPP1) were inversely regulated by IGFBP5 and Bcl-3. BT474 cells also responded to stromal cells by downregulating IGFBP5 and upregulating the P-AKT, Bcl-3 and IGF1R levels, whereas T47D cells did not show any of these responses. In conclusion, our data suggest that, by targeting IGFBP5 expression in ERα-positive breast cancer cells, such as MCF-7 cells, MSCs and CAFs are able to orchestrate a variety of events, particularly activation of the PI3K/AKT pathway, upregulation of Bcl-3 expression and desensitization to anti-estrogen.
authors.affiliation: Clinic for Gynecology, Martin Luther University Halle-Wittenberg, Halle(Saale), Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leyh
authors.affiliation: Clinic for Gynecology, Martin Luther University Halle-Wittenberg, Halle(Saale), Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Dittmer
authors.affiliation: Clinic for Gynecology, Martin Luther University Halle-Wittenberg, Halle(Saale), Germany.
authors.forename: Theresia
authors.initials: T
authors.lastname: Lange
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Clinic for Gynecology, Martin Luther University Halle-Wittenberg, Halle(Saale), Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Dittmer
mesh_terms: D000081242:B-Cell Lymphoma 3 Protein; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology*; D005347:Fibroblasts / Q000473:pathology*; D000077267:Fulvestrant; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism*; D061986:MCF-7 Cells; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D065171:Estrogen Receptor Antagonists; D018975:Insulin-Like Growth Factor Binding Protein 5; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000077267:Fulvestrant; D004958:Estradiol
keywords: anti-estrogen resistance; carcinoma-associated fibroblasts; fulvestrant; mesenchymal stem cells; stromal cells