Role of p53 codon 72 arginine allele in cell survival in vitro and in the clinical outcome of patients with advanced breast cancer.
BACKGROUND
The p53 codon 72 polymorphism, which results in either an arginine or proline residue, plays a different role in vitro and in vivo in cell survival and drug resistance. We verified, in vitro, the impact of the arginine allele on cell survival under normoxia and hypoxia, and investigated in vivo the role of p53 codon 72 arginine homozygosity in the clinical outcome of advanced breast cancer patients.


METHODS
Tumors at advanced stages grow in vivo in a hypoxic environment, and we mimicked such conditions in vitro using p53 null breast cancer cells transfected with either the arginine or proline allele. We also analyzed in vivo the p53 codon 72 genotype status of advanced breast cancer patients.


RESULTS
In vitro transfection of the arginine allele induced higher cell death under normoxia, whereas cell death was greater in proline-transfected cells under hypoxia. The arginine allele upregulated BCRP-I, a hypoxia response gene, which increases drug resistance. Metastatic breast cancer patients homozygous for arginine had a significantly shorter time to progression and overall survival than those with heterozygous arginine/proline tumors.


CONCLUSIONS
We provide a molecular explanation for the association of the arginine allele with tumor aggressiveness and treatment resistance in advanced breast cancer.
Vannini
I
I
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy.
Zoli
W
W
Tesei
A
A
Rosetti
M
M
Sansone
P
P
Storci
G
G
Passardi
A
A
Massa
I
I
Ricci
M
M
Gusolfino
D
D
Fabbri
F
F
Ulivi
P
P
Brigliadori
G
G
Amadori
D
D
Bonafe
M
M
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D001120:Arginine / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D003062:Codon / Q000235:genetics*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011392:Proline / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D003062:Codon; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D001120:Arginine; D011392:Proline