The BH3-only protein Bad confers breast cancer taxane sensitivity through a nonapoptotic mechanism.
Antimitotic agents such as taxanes (paclitaxel and docetaxel) have greatly advanced the treatment of breast cancer, although variable patient response and drug toxicity are major limitations. Lack of validated predictive markers for taxane responsiveness precludes a priori identification of patients who are most likely to respond to treatment; thus, a subset of patients endure toxic side effects with marginal benefit. Mechanistic insights into taxane therapeutic activity may lead to rational therapeutic improvements. In this paper we report that the proapoptotic BH3-only protein Bad has a major role in taxane-induced cell death in vitro, and clinically is a prognostic indicator for overall survival of breast cancer patients after adjuvant taxane chemotherapy. Unexpectedly, Bad did not induce the mitochondrial apoptotic machinery in response to taxane treatment. Instead, Bad indirectly facilitated cell death by stimulating cellular proliferation. As dividing cells are the targets of taxane therapy, Bad-stimulated proliferation may be a marker of taxane sensitivity. Our studies indicate that quantification of Bad protein levels may have value as a diagnostic tool. They also suggest that cells expressing Bad are more sensitive to taxanes because of their altered cell cycle dynamics and reveal a clinically relevant proliferative role of Bad in breast cancer.
Craik
A C
AC
Department of Biochemistry, School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada.
Veldhoen
R A
RA
Czernick
M
M
Buckland
T W
TW
Kyselytzia
K
K
Ghosh
S
S
Lai
R
R
Damaraju
S
S
Underhill
D A
DA
Mackey
J R
JR
Goping
I S
IS
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D001943:Breast Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D051025:bcl-Associated Death Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C494819:BAD protein, human; C494811:BCL2L1 protein, human; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D017239:Paclitaxel