J Huang1,2, P Woods1, D Normolle3, J P Goff1, P V Benos4, C J Stehle1, R A Steinman5,6. 1. Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Suite 2.26f Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. 2. School of Medicine, Tsinghua University, Beijing, China. 3. Department of Biostatistics, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, USA. 4. Department of Computational Biology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, USA. 5. Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Suite 2.26f Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. Steinman@pitt.edu. 6. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, USA. Steinman@pitt.edu.
Abstract
PURPOSE: Breast cancers have a poorer prognosis if estrogen receptor expression was lost during recurrence. It is unclear whether this conversion is cell autonomous or whether it can be promoted by the microenvironment during cancer dormancy. We explored the ability of marrow-derived stromal cell lines to arrest co-cultured breast cancer cells and suppress estrogen receptor alpha (ER) expression during arrest, facilitating the emergence of estrogen-independent breast cancer clones. METHODS: Cancer cell growth, ER protein, microRNA, and mRNA levels were measured in breast cancer cell lines exposed to conditioned medium from marrow stromal lines in the presence and absence of estrogen and of signaling pathway modulators. RESULTS: We demonstrate that paracrine signaling from the stromal cell line HS5 downregulated ER in T47D and MCF7 breast cancer cells. This occurred at the mRNA level and also through decreased ER protein stability. Additionally, conditioned medium (CM) from HS5 arrested the breast cancer cells in G0/G1 in part through interleukin-1 (IL1) and inhibited cancer cell growth despite the activation of proliferative pathways (Erk and AKT) by the CM. Similar findings were observed for CM from the hFOB 1.19 osteoblastic cell line but not from two other fibroblastic marrow lines, HS27A and KM101. HS5-CM inhibition of MCF7 proliferation could not be restored by exogenous ER, but was restored by the IL1-antagonist IL1RA. In the presence of IL1RA, HS5-CM activation of AKT and Erk enabled the outgrowth of breast cancer cells with suppressed ER that were fulvestrant-resistant and estrogen-independent. CONCLUSIONS: We conclude that marrow-derived stromal cells can destabilize estrogen receptor protein to convert the ER status of growth-arrested ER+ breast cancer cell lines. The balance between stromal pro- and anti-proliferative signals controlled the switch from a dormant phenotype to estrogen-independent cancer cell growth.
PURPOSE:Breast cancers have a poorer prognosis if estrogen receptor expression was lost during recurrence. It is unclear whether this conversion is cell autonomous or whether it can be promoted by the microenvironment during cancer dormancy. We explored the ability of marrow-derived stromal cell lines to arrest co-cultured breast cancer cells and suppress estrogen receptor alpha (ER) expression during arrest, facilitating the emergence of estrogen-independent breast cancer clones. METHODS:Cancer cell growth, ER protein, microRNA, and mRNA levels were measured in breast cancer cell lines exposed to conditioned medium from marrow stromal lines in the presence and absence of estrogen and of signaling pathway modulators. RESULTS: We demonstrate that paracrine signaling from the stromal cell line HS5 downregulated ER in T47D and MCF7 breast cancer cells. This occurred at the mRNA level and also through decreased ER protein stability. Additionally, conditioned medium (CM) from HS5 arrested the breast cancer cells in G0/G1 in part through interleukin-1 (IL1) and inhibited cancer cell growth despite the activation of proliferative pathways (Erk and AKT) by the CM. Similar findings were observed for CM from the hFOB 1.19 osteoblastic cell line but not from two other fibroblastic marrow lines, HS27A and KM101. HS5-CM inhibition of MCF7 proliferation could not be restored by exogenous ER, but was restored by the IL1-antagonist IL1RA. In the presence of IL1RA, HS5-CM activation of AKT and Erk enabled the outgrowth of breast cancer cells with suppressed ER that were fulvestrant-resistant and estrogen-independent. CONCLUSIONS: We conclude that marrow-derived stromal cells can destabilize estrogen receptor protein to convert the ER status of growth-arrested ER+ breast cancer cell lines. The balance between stromal pro- and anti-proliferative signals controlled the switch from a dormant phenotype to estrogen-independent cancer cell growth.
Authors: Donna M Sosnoski; Robert J Norgard; Cassidy D Grove; Shelby J Foster; Andrea M Mastro Journal: Clin Exp Metastasis Date: 2015-03-08 Impact factor: 5.150
Authors: Sofie Svensson; Karin Jirström; Lisa Rydén; Göran Roos; Stefan Emdin; Michael C Ostrowski; Göran Landberg Journal: Oncogene Date: 2005-06-23 Impact factor: 9.867
Authors: Laurien D C Hoefnagel; Marc J van de Vijver; Henk-Jan van Slooten; Pieter Wesseling; Jelle Wesseling; Pieter J Westenend; Joost Bart; Cornelis A Seldenrijk; Iris D Nagtegaal; Joost Oudejans; Paul van der Valk; Petra van der Groep; Elisabeth G E de Vries; Elsken van der Wall; Paul J van Diest Journal: Breast Cancer Res Date: 2010-09-23 Impact factor: 6.466
Authors: Molly M Morgan; Linda A Schuler; Jordan C Ciciliano; Brian P Johnson; Elaine T Alarid; David J Beebe Journal: Integr Biol (Camb) Date: 2020-03-06 Impact factor: 2.192
Authors: Johanna M Buschhaus; Shrila Rajendran; Brock A Humphries; Alyssa C Cutter; Ayşe J Muñiz; Nicholas G Ciavattone; Alexander M Buschhaus; Tatiana Cañeque; Zeribe C Nwosu; Debashis Sahoo; Avinash S Bevoor; Yatrik M Shah; Costas A Lyssiotis; Pradipta Ghosh; Max S Wicha; Raphaël Rodriguez; Gary D Luker Journal: Oncogene Date: 2022-06-22 Impact factor: 8.756
Authors: David K Lung; Jay W Warrick; Peiman Hematti; Natalie S Callander; Christina J Mark; Shigeki Miyamoto; Elaine T Alarid Journal: Endocrinology Date: 2019-10-01 Impact factor: 4.736
Authors: María Inés Diaz Bessone; María José Gattas; Tomás Laporte; Max Tanaka; Marina Simian Journal: Front Endocrinol (Lausanne) Date: 2019-08-08 Impact factor: 5.555