Abstract 581: Gene-expression signatures of anoikis induced by doxorubicin, docetaxel or transfection with TAp73α
Authors: Alsafadi Samar , Lazar Vladimir , Vassal Gilles , André Fabrice , Ahomadegbe Jean-Charles 
Published: June 2012

Anoikis, a type of apoptosis induced by inadequate cell-matrix interaction, is involved in a wide diversity of tissue-homeostatic and oncogenic processes. Resistance to anoikis is a common feature of many tumor cells that has been associated with tumor progression and metastasis. Recently, we have shown that doxorubicin and docetaxel induce anoikis associated with different post-translational modification profiles of p53 and p73. By contrast, anoikis induced by transfection with TAp73α, a homolog of p53, is associated with a similar post-translational modification profile to that induced by doxorubicin.

In this study, we used RNA microarray technology to determine the cellular response signals to treatment with doxorubicin, docetaxel, or transfection with TAp73α in MDA-MB361 (mutated p53) and ZR75-1 (Wt-p53) breast cancer cell lines. We designed two models of analysis. The first model is based on the comparison of gene expression profiles of treated adherent cells vs. untreated adherent cells. This model represents the primary response signatures. The second model compares the treated detached cells to the treated adherent cells representing anoikis signatures.

Our results indicate that, though the primary responses vary noticeably, doxorubicin and docetaxel share certain clustering similarity while the TAp73α shows a unique signature. By contrast, the analysis of anoikis signatures reveals two hierarchical groups: the first group consists of doxorubicin and TAp73α with a considerable homogeneity while the second group comprises only docetaxel.

We tried to determine the most interesting common genes implicated in anoikis whatever the cell line. For this purpose, we selected genes whose expression variations were statistically significant (p&lt;0.05; Limma model) with expression ratios values (detached cells/adherent cells) greater than 4 (for overexpressed genes in detached cells), or lower than 0.25 (for under-expressed genes in detached cells). We report a set of 351 genes that are modified according to these stringent conditions. Surprisingly, only seven of these genes (2%) are under-expressed in detached cells, all others (98%) are overexpressed in these cells. No genes are common to the conditions “TAp73α” and “docetaxel". CD86 and TMEFF2 are the two common genes to the conditions “TAp73α” and “doxorubicin". ASPM is the unique common gene to the conditions “doxorubicin” and “docetaxel", whatever the cell line.

In conclusion, although the action mechanism of the three agents is very different, doxorubicin and TAp73α use probably the same mechanism for inducing anoikis while docetaxel has a unique mechanism. The three genes implicated in anoikis signatures, whatever the cell lines, are currently being validated in our laboratory.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 581. doi:10.1158/1538-7445.AM2011-581