beta 1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts [electronic resource].
- Published
- Berkeley, Calif. : Lawrence Berkeley National Laboratory, 2008.
Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy. - Additional Creators
- Lawrence Berkeley National Laboratory and United States. Department of Energy. Office of Scientific and Technical Information
Access Online
- Restrictions on Access
- Free-to-read Unrestricted online access
- Summary
- β1 integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of β1 integrin signaling. We showed previously that β1 integrin inhibitory antibodies, AIIB2, enhance apoptosis and decrease growth in human breast cancer cells in 3 dimensional laminin-rich extracellular matrix (3D lrECM) cultures and in vivo. Here we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used 3D lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in 3D lrECM. Colonies were assayed for apoptosis and β1 integrin/Akt signaling pathways were evaluated using western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in 3D lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down regulating Akt in breast cancer colonies in 3D lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared to either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We showed previously that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo.
- Report Numbers
- E 1.99:lbnl-434e
lbnl-434e - Other Subject(s)
- Note
- Published through SciTech Connect.
06/02/2008.
"lbnl-434e"
Cancer Research 68 11 ISSN 0008-5472; CNREA8 FT
Bissell, Mina J.; Park, Chong J.; Zhang, Hui J.; Park, Catherine C.; Yao, Evelyn S.
Life Sciences Division - Funding Information
- DE-AC02-05CH11231
View MARC record | catkey: 13809608