The Role of Akt and its Substrates in Resistance of Breast Cancer to Trastuzumab
Abstract
We have crossed the MMTV-myr-Akt1 transgenic mice (which express constitutively active Akt1 in the mammary gland) with MMTV-c-ErbB2 transgenic mice to evaluate the role of Akt1 activation in ErbB2-induced mammary carcinoma. Bitransgenic MMTV-c-ErbB2, MMTV-myr-Akt1 mice develop mammary tumors twice as quickly as the MMTV-c-ErbB2 mice. Histology and activated caspase 3 immunohistochemistry demonstrated that the bitransgenic tumors were less organized and had fewer apoptotic cells, however many bitransgenic tumors displayed areas of extensive necrosis as compared to the tumors from MMTV-c-ErbB2 mice. The two tumor types demonstrate dramatically different expression and activation of EGFR family members as well as different metabolic profiles. c-ErbB2 tumors demonstrate overexpression of EGFR, ErbB2, ErbB3 and ErbB4 and activation/phosphorylation of both ErbB2 and ErbB3, underscoring the importance of the entire EGFR family in ErbB2-induced tumorigenesis. Tumors from bitransgenic mice demonstrate overexpression of the myr-Akt1 and ErbB2 transgenes, however there was dramatically less overexpression and phosphorylation of ErbB3, the phosphorylation of ErbB2 was diminished, the level of EGFR protein was decreased and ErbB4 protein was undetectable. There was also an observable attenuation in a subset of tyrosine-phosphorylated scaffolding molecules as well as Src in the bitransgenic tumors as compared to the c-ErbB2 tumors. Finally, the bitransgenic tumors were metabolically more active as indicated by increased GLUT1 glucose transporter expression, elevated lactate production and decrease intracellular glucose (suggesting increased glycolysis). The reduction in signaling downstream of ErbB2 when Akt is activated suggest a possible mechanism by which tumor cells can become resistant to ErbB2-targeted therapies, necessitating therapies that target oncogenic signaling events downstream of ErbB2.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2008
- Accession Number
- ADA493661
Entities
People
- Christian D. Young
Organizations
- University of Colorado Boulder