Abstract
Our present work offers a new means by which cancer cells become resistant to anti-cancer treatments and mechanism-driven approaches for overcoming such resistance. Specifically, here we demonstrate a previously unrecognized mechanism of tamoxifen (TMX) resistance distinct from loss of estrogen receptor on basal-like (triple negative) breast cancer cells, which are among the most challenging tumors to treat with current therapies. Our present finding emerged from trying to understand the puzzling differences in regulation of receptor tyrosine kinase (RTK) degradation in normal progenitor cells and in breast cancer cells. When glial progenitor cells become slightly more (15-20%) oxidized, such as by exposing them to TMX, we find sequential activation of Fyn (a member of the Src-family of kinases) and c-Cbl (an E3 ubiquitin ligase) is activated. Phosphorylation of c-Cbl causes ubiquitylation of its target proteins and thus increases the degradation of its target proteins, such as particular RTKs, including the epidermal growth factor receptor (EGFR, our specific target in this study). In contrast to normal progenitor cells, basal-like breast cancer cells exposed to TMX show increased Fyn activation but no increase in c-Cbl phosphorylation. We now have found that oxidation-induced activation of c-Cbl in basal-like breast cancer cells is inhibited due to expression of Cdc42. Cdc42 sequestered c-Cbl, prevented its activation and prevented EGFR from being degraded. Restoration of c-Cbl function, by genetically or pharmacologically inhibiting Cdc42 activation, reduced EGFR levels in these cells. More critically, restoring c-Cbl function sensitized these cells to TMX both in vitro and in vivo. Analysis of tumor growth in vivo showed that reducing the levels of Cdc42 both reduced the size of tumors and made them more sensitive to TMX. The results provide a novel defense mechanism that basal-like breast cancer cells utilize to prevent EGFR degradation which may have high relevance to treatment of these tumors. Of particular importance is the ability of Cdc42 knockdown to confer TMX sensitivity on these otherwise resistant tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 769. doi:1538-7445.AM2012-769
- ©2012 American Association for Cancer Research
Volume 72, Issue 8 Supplement
