Tissue-type plasminogen activator is upregulated in metastatic breast cancer cells exposed to insulin-like growth factor-I.
The insulin-like growth factor (IGF) system plays an important role in breast tumorigenesis. Breast cancer cells express the type I IGF receptor (IGF-IR) and respond to IGFs in the environment. Tissue-type plasminogen activator (tPA) has been shown to be associated with neoplastic transformation and the invasive phenotype for highly aggressive tumors; however, its role in breast cancer remains unclear. We asked whether there is a relationship between the IGF system and tPA in estrogen receptor-negative breast cancer cells that could contribute to invasion. When MDA-MB-435s breast cancer cells were exposed to IGF-I, tPA messenger RNA (mRNA) was upregulated in a time-dependent fashion. Tissue-type plasminogen activator protein accumulation was also increased in a similar manner. The invasiveness of MDA-MB-435s cells was enhanced in the presence of IGF-I. When the MDA-MB-435s cells were stably transfected with an antisense IGF-IR expression construct, the transfectants expressed high levels of IGF-IR antisense, dramatically reduced levels of endogenous IGF-IR, and a decrease in relative staining intensity for IGF-IR protein. A marked suppression in tPA mRNA expression occurred in MDA-MB-435s cells accompanying inhibition of IGF-IR. When cells carrying the antisense IGF-IR expression construct were exposed to IGF-I, tPA protein accumulation was significantly lower than that of control transfected cells. To our knowledge, this study is the first to show a relationship between the IGF system and tPA. Strategies that target the IGF/tPA pathway could provide alternative treatments for patients with certain types of metastatic breast cancer.
Chernicky
Cheryl L
CL
Department of Obstetrics and Gynecology, University Hospitals of Cleveland, University MacDonald Women's Hospital, Cleveland, OH 44106, USA. cheryl.chernicky@uhhs.com
Yi
Lijuan
L
Tan
Huiqing
H
Ilan
Judith
J
D000328:Adult; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D044584:Carcinoma, Ductal / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor / Q000737:chemistry / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011960:Receptors, Estrogen / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D011960:Receptors, Estrogen; D007334:Insulin-Like Growth Factor I; D010959:Tissue Plasminogen Activator