Metastatic
breast cancer is an incurable disease, often characterized by poor response to standard
chemotherapy, which is mainly based on
anthracyclines and
taxanes. Thus, increasing
tumor cell sensitivity to these agents is an attractive goal towards improving the clinical management of this disease. The present study investigates the effects of
signal transducer and activator of transcription 3 (Stat3) inhibition on the response of the highly metastatic MDA-MB-231 human breast
adenocarcinoma cell line to
doxorubicin (DOX). Stat3 is a
transcription factor often constitutively activated in
breast tumors and
cancer cell lines, and is thought to contribute to malignant transformation and progression by transactivation of a host of target genes involved in cell proliferation and survival, angiogenesis and invasiveness. Our results indicate that (a) untreated MDA-MB-231 cells express higher baseline levels of (activated) pTyr(705)Stat3, that are further upregulated following exposure to DOX, than the non-metastatic MCF-7 cell line; (b) inhibiting the Stat3 signaling pathway, by exposure to the
tyrphostin AG490 (an inhibitor of the upstream activating
Janus kinases), by transfection with a dominant-negative form of Stat3 or by treatment with
satraplatin (a tetravalent
platinum derivative that inhibits Stat3 activation), increases
breast cancer cell response to the proapoptotic effect of DOX (to different extents). In addition, the latter two approaches have been shown to interfere with expression of one or more antiapoptotic
proteins. Overall, these observations suggest that suppression of Stat3 signaling may provide a potential therapeutic approach to overcoming DOX resistance in metastatic
breast cancer cells.