Extracellular matrix, Rac1 signaling, and estrogen-induced proliferation in MCF-7 breast cancer cells.
Estrogen receptor positive (ER+), estrogen (E) responsive MCF-7 breast cancer cells cultured on the extracellular matrix (ECM) protein laminin (LM), exhibit significantly reduced E-induced proliferation compared with cells cultured on collagen I (Col I) that is not due to a loss of ER. Based on reported differences in integrin-activated pathways on Col I vs. LM, we investigated the potential role of Rac1/c-jun-N-terminal kinase (JNK) activation and downstream regulation of cyclin D1 by E on Col I vs.LM. E-induced proliferation was increased on LM in MCF-7 cells expressing constitutively active Rac1 (CA Rac1) and decreased in dominant negative Rac1-(DN Rac1) expressing cells on Col I. siRNA knockdown established the specificity and requirement for Rac1 activation for E-induced regulation of cyclin D1. More robust c-Jun activation occurred on Col I than on LM and E-induced proliferation was abolished after treatment with a JNK inhibitor. These results provide evidence that Rac1/JNK/c-Jun activation promotes E-induced proliferation on Col I and reduced Rac1/JNK/c-Jun activation on LM contributes significantly to reduced E-induced proliferation in MCF-7 cells on LM. These results identify a novel role for extracellular matrix (ECM)-integrin regulation of Rac1-JNK pathway in E-regulated proliferation in ER+ breast cancer cells. These findings suggest that tumor stromal environment, i.e., ECM composition, may contribute to loss of E regulation in ER+ breast cancers. Defining molecular markers for early identification of ER+ tumors that are ER+ but antiestrogen resistant would allow the design and use of alternative therapies to inhibit tumor growth and improve survival.
Xie
J-W
JW
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Haslam
S Z
SZ
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D004967:Estrogens; D007797:Laminin; C107953:RAC1 protein, human; C411563:RAC3 protein, human; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D019938:Cyclin D1; D003094:Collagen; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein