p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer.
Studies on the role of TP53 mutation in breast cancer response to chemotherapy are conflicting. Here, we show that, contrary to dogma, MMTV-Wnt1 mammary tumors with mutant p53 exhibited a superior clinical response compared to tumors with wild-type p53. Doxorubicin-treated p53 mutant tumors failed to arrest proliferation, leading to abnormal mitoses and cell death, whereas p53 wild-type tumors arrested, avoiding mitotic catastrophe. Senescent tumor cells persisted, secreting senescence-associated cytokines exhibiting autocrine/paracrine activity and mitogenic potential. Wild-type p53 still mediated arrest and inhibited drug response even in the context of heterozygous p53 point mutations or absence of p21. Thus, we show that wild-type p53 activity hinders chemotherapy response and demonstrate the need to reassess the paradigm for p53 in cancer therapy.
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
James G
JG
Jackson
Vinod
V
Pant
Qin
Q
Li
Leslie L
LL
Chang
Alfonso
A
Quintás-Cardama
Daniel
D
Garza
Omid
O
Tavana
Peirong
P
Yang
Taghi
T
Manshouri
Yi
Y
Li
Adel K
AK
El-Naggar
Guillermina
G
Lozano
D000375:Aging / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D051155:Wnt1 Protein / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; D016159:Tumor Suppressor Protein p53; D051155:Wnt1 Protein; D004317:Doxorubicin