Cooperative interactions of HER-2 and HPV-16 oncoproteins in the malignant transformation of human mammary epithelial cells.
To better understand the mechanisms of transformation by the oncogene HER-2, we transduced the human mammary epithelial (HME) cell line MCF-10A with HER-2 and developed a cell line that appeared to moderately overexpress HER-2. These MCF-10HER-2 cells were unable to grow in the absence of epidermal growth factor (EGF). However, coexpression of HER-2 with the HPV-16 oncoproteins E6 and E7 resulted in EGF-independent cells that expressed very high levels of constitutively activated HER-2. Interestingly, coexpression of E7 with HER-2 resulted in cells that were EGF-independent for growth but did not express HER-2 to high levels, and coexpression of E6 with HER-2 resulted in cells expressing higher levels of HER-2, which were still dependent on EGF for growth and survival. The MCF-10HER-2E7 and HER-2/E6E7 cells exhibited constitutive activation of a form of epidermal growth factor receptor (EGFR) that had a faster electrophoretic mobility than EGFR activated by exogenous growth factors. Exposure of cells with EGFR activation to ZD1839 (Iressa), at concentrations specific for EGFR, had little or no influence on proliferation of cells with amplified HER-2 but little or no EGFR. These results indicate that HER-2, E6, and E7 cooperate with endogenous EGFR to yield fully transformed cells.
Woods Ignatoski
Kathleen M
KM
Department of Radiation Oncology and The Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
Dziubinski
Michele L
ML
Ammerman
Cheryl
C
Ethier
Stephen P
SP
D001943:Breast Neoplasms; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000378:metabolism*; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis*; D050725:Papillomavirus E7 Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D012097:Repressor Proteins / Q000096:biosynthesis*
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D012097:Repressor Proteins; C068651:E6 protein, Human papillomavirus type 16; C059731:oncogene protein E7, Human papillomavirus type 16