In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 24_Supplement ( 2009-12-15), p. 2161-2161
Abstract:
Whether or not certain subtypes of mammary tumors specifically rely on a limited number of anti-apoptotic mechanisms for their maintenance, and how therapy might affect these mechanisms, is currently ill characterized.We have analyzed published gene-expression profiles of breast cancer patients for which HER2 status, evaluated by immunohistochemistry, was also available. A statistically significant enrichment in the expression of Mcl-1 in HER2 amplified breast tumors, compared to other breast tumors, was found.In vitro, knock down of Mcl-1 expression by RNA interference proved sufficient to induce apoptosis in the HER2 amplified cell line BT474. Combined RNA interference experiments showed that apoptosis induced by Mcl-1 knock down in these cells (ie, their “Mcl-1 dependence”) relied on the expression of the pro-apoptotic BH3-only protein Bim. This indicates that the Bim/Mcl-1 balance (possibly regulated by direct physical interactions between these two proteins) constitutes an integrating point towards which the numerous survival pathways that are known to lie downstream of HER2 should converge, to the very least in these cells.While seeking for signaling pathways that might significantly affect Mcl-1 dependence downstream of HER2, using diverse small molecule inhibitors, we found that mTORC1 inhibition in BT474 cells not only leaves Mcl-1 expression levels unaltered, but also prevents induction of apoptosis by Mcl-1 depletion. mTORC1 inhibition enhances the activity of the survival kinases Akt and ERK (p44 and p42). HER2 signaling is involved in this activation, since it is prevented by trastuzumab treatment.These data suggest that, due to the structure of the signaling network mTORC1 is embedded in (which includes the HER2 driven negative feedback loop described here), its activity locks HER2 amplified cells in a Mcl-1 dependent state. They also imply that combining inhibitors of mTORC1 with inhibitors of the HER2 pathway (such as trastuzumab) might restrain the effects on cell survival of the former, and enhance their clinical efficiency in HER2 amplified breast cancers. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2161.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/0008-5472.SABCS-09-2161
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2009
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
