PTH-related protein upregulates integrin alpha6beta4 expression and activates Akt in breast cancer cells.
Breast cancer is the most common carcinoma that metastasizes to bone. Tumor-produced parathyroid hormone-related protein (PTHrP), a known stimulator of osteoclastic bone resorption, is a major mediator of the osteolytic process in breast cancer. We have previously shown that PTHrP increases breast cancer cell proliferation, survival, migration, and pro-invasive integrin alpha6beta4 expression. To determine the role of integrin alpha6beta4 in these PTHrP-mediated effects, we utilized two strategies to modulate expression of the alpha6 and beta4 subunits in parental and PTHrP-overexpressing MDA-MB-231 and MCF-7 cells: overexpression of alpha6beta4 by transfection with constructs encoding the alpha6 and beta4 subunits, and suppression of endogenous alpha6beta4 expression by transfection with siRNAs targeting these subunits. We now show that the effects of PTHrP are mediated via upregulation of integrin alpha6beta4 expression. We also show that integrin alpha6beta4 expression is modulated at the mRNA level, indicating a transcriptional and/or post-transcriptional mechanism of action for PTHrP. PTHrP expression also increased the levels of phosphorylated Akt, with a consequent increase in the levels of phosphorylated (inactive) glycogen synthase kinase-3 (GSK-3). The role of PTHrP in breast cancer growth and metastasis may thus be mediated via upregulation of integrin alpha6beta4 expression and Akt activation, with consequent inactivation of GSK-3.
Shen
Xiaoli
X
Department of Pharmacology and Toxicology, and Sealy Center for Molecular Science, University of Texas Medical Branch, 10th and Market Streets, Galveston, TX 77555, USA.
Falzon
Miriam
M
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D018076:DNA, Complementary / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D039161:Integrin alpha6beta4 / Q000235:genetics / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
D018076:DNA, Complementary; D039161:Integrin alpha6beta4; D044162:Parathyroid Hormone-Related Protein; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3