The high risk of developing cancer seen in human genetic diseases that resemble accelerated aging provides support for a tumorigenic contribution of the mechanisms and genes responsible for regulating life span and aging. We therefore speculated that the WRN gene (encoding RECQL2, a DNA helicase), the germline mutation of which causes the progeroid disorder Werner syndrome, may be associated with breast tumorigenesis. This hypothesis was tested in this case-control study of 935 primary breast cancer patients and 1,545 healthy controls by examining single-nucleotide polymorphisms (SNPs) in WRN. We were also interested in knowing whether any identified association between WRN and breast cancer was modified by reproductive risk factors reflecting susceptibility to estrogen exposure. Our hypothesis is that because estrogen is known to promote breast cancer development via its mitogenic effect leading to cell proliferation, and because WRN is an essential gene, as its suboptimal function leads to a severe decrease in proliferation, estrogen stimulation may have a protective effect on cells harboring variant WRN, allowing them to survive and proliferate for the prolonged period needed for tumor formation. Support for this hypothesis came from the following observations: (a) one SNP in WRN was significantly associated with breast cancer risk (P = 0.002); (b) haplotype and diplotype analyses, based on different combinations of multiple SNPs in WRN, revealed a strong association with breast cancer risk; (c) this association between risk and putative high-risk genotypes was stronger and more significant in women with a longer interval between menarche and first full-term pregnancy; and (d) the protective effect conferred by having a higher number of full-term pregnancy was only significant in women with homozygous or heterozygous wild-type WRN genotypes. This study provides support for the tumorigenic role of WRN in breast cancer development, suggesting that breast cancer can be driven by the aging associated with variant WRN, the tumorigenic contribution of which might be enhanced as a result of increased cell growth due to estrogen exposure.