Abstract
Inherent and acquired therapeutic resistance in breast cancer remains a major clinical challenge. In human breast cancer samples, overexpression of the oncogenic transcription factor FoxM1 has been suggested to be a marker of poor prognosis. In this study, we report that FoxM1 overexpression confers resistance to the human epidermal growth factor receptor 2 monoclonal antibody Herceptin and microtubule-stabilizing drug paclitaxel, both as single agents and in combination. FoxM1 altered microtubule dynamics to protect tumor cells from paclitaxel-induced apoptosis. Mechanistic investigations revealed that the tubulin-destabilizing protein Stathmin, whose expression also confers resistance to paclitaxel, is a direct transcriptional target of FoxM1. Significantly, attenuating FoxM1 expression by small interfering RNA or an alternate reading frame (ARF)-derived peptide inhibitor increased therapeutic sensitivity. Our findings indicate that targeting FoxM1 could relieve therapeutic resistance in breast cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5054-5063 |
| Number of pages | 10 |
| Journal | Cancer Research |
| Volume | 70 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 15 2010 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
FoxM1 mediates resistance to herceptin and paclitaxel. / Carr, Janai R.; Park, Hyun Jung; Wang, Zebin; Kiefer, Megan M.; Raychaudhuri, Pradip.
In: Cancer Research, Vol. 70, No. 12, 15.06.2010, p. 5054-5063.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - FoxM1 mediates resistance to herceptin and paclitaxel
AU - Carr, Janai R.
AU - Park, Hyun Jung
AU - Wang, Zebin
AU - Kiefer, Megan M.
AU - Raychaudhuri, Pradip
PY - 2010/6/15
Y1 - 2010/6/15
N2 - Inherent and acquired therapeutic resistance in breast cancer remains a major clinical challenge. In human breast cancer samples, overexpression of the oncogenic transcription factor FoxM1 has been suggested to be a marker of poor prognosis. In this study, we report that FoxM1 overexpression confers resistance to the human epidermal growth factor receptor 2 monoclonal antibody Herceptin and microtubule-stabilizing drug paclitaxel, both as single agents and in combination. FoxM1 altered microtubule dynamics to protect tumor cells from paclitaxel-induced apoptosis. Mechanistic investigations revealed that the tubulin-destabilizing protein Stathmin, whose expression also confers resistance to paclitaxel, is a direct transcriptional target of FoxM1. Significantly, attenuating FoxM1 expression by small interfering RNA or an alternate reading frame (ARF)-derived peptide inhibitor increased therapeutic sensitivity. Our findings indicate that targeting FoxM1 could relieve therapeutic resistance in breast cancer.
AB - Inherent and acquired therapeutic resistance in breast cancer remains a major clinical challenge. In human breast cancer samples, overexpression of the oncogenic transcription factor FoxM1 has been suggested to be a marker of poor prognosis. In this study, we report that FoxM1 overexpression confers resistance to the human epidermal growth factor receptor 2 monoclonal antibody Herceptin and microtubule-stabilizing drug paclitaxel, both as single agents and in combination. FoxM1 altered microtubule dynamics to protect tumor cells from paclitaxel-induced apoptosis. Mechanistic investigations revealed that the tubulin-destabilizing protein Stathmin, whose expression also confers resistance to paclitaxel, is a direct transcriptional target of FoxM1. Significantly, attenuating FoxM1 expression by small interfering RNA or an alternate reading frame (ARF)-derived peptide inhibitor increased therapeutic sensitivity. Our findings indicate that targeting FoxM1 could relieve therapeutic resistance in breast cancer.
UR - http://www.scopus.com/inward/record.url?scp=77953744612&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953744612&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-0545
DO - 10.1158/0008-5472.CAN-10-0545
M3 - Article
C2 - 20530690
AN - SCOPUS:77953744612
VL - 70
SP - 5054
EP - 5063
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 12
ER -