Estrogen Drives Cellular Transformation and Mutagenesis in Cells Expressing the Breast Cancer-Associated R438W DNA Polymerase Lambda Protein.
Repair of DNA damage is critical for maintaining the genomic integrity of cells. DNA polymerase lambda (POLL/Pol λ) is suggested to function in base excision repair (BER) and nonhomologous end-joining (NHEJ), and is likely to play a role in damage tolerance at the replication fork. Here, using next-generation sequencing, it was discovered that the POLL rs3730477 single-nucleotide polymorphism (SNP) encoding R438W Pol λ was significantly enriched in the germlines of breast cancer patients. Expression of R438W Pol λ in human breast epithelial cells induces cellular transformation and chromosomal aberrations. The role of estrogen was assessed as it is commonly used in hormone replacement therapies and is a known breast cancer risk factor. Interestingly, the combination of estrogen treatment and the expression of the R438W Pol λ SNP drastically accelerated the rate of transformation. Estrogen exposure produces 8-oxoguanine lesions that persist in cells expressing R438W Pol λ compared with wild-type (WT) Pol λ-expressing cells. Unlike WT Pol λ, which performs error-free bypass of 8-oxoguanine lesions, expression of R438W Pol λ leads to an increase in mutagenesis and replicative stress in cells treated with estrogen. Together, these data suggest that individuals who carry the rs3730477 POLL germline variant have an increased risk of estrogen-associated breast cancer.



The Pol λ R438W mutation can serve as a biomarker to predict cancer risk and implicates that treatment with estrogen in individuals with this mutation may further increase their risk of breast cancer. Mol Cancer Res; 14(11); 1068-77. ©2016 AACR.
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut. antonia.nemec@med.fsu.edu joann.sweasy@yale.edu.
Antonia A
AA
Nemec
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
Korie B
KB
Bush
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
Jamie B
JB
Towle-Weicksel
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
B Frazier
BF
Taylor
Department of Pediatrics, Yale University, New Haven, Connecticut.
Vincent
V
Schulz
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.|Division of Molecular and Cellular Oncology, UCLA, Los Angeles, California.
Joanne B
JB
Weidhaas
Departmentof Pathology, Yale University, New Haven, Connecticut.
David P
DP
Tuck
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut. antonia.nemec@med.fsu.edu joann.sweasy@yale.edu.
Joann B
JB
Sweasy
D001943:Breast Neoplasms / Q000139:chemically induced* / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics*; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000235:genetics*; D004260:DNA Repair; D004967:Estrogens / Q000009:adverse effects*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006147:Guanine / Q000031:analogs & derivatives; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020641:Polymorphism, Single Nucleotide
D004967:Estrogens; C024829:8-hydroxyguanine; D006147:Guanine; C415367:DNA polymerase beta2; D019951:DNA Polymerase beta