A genetic study was conducted to determine if activated Stat5a contributes to mammary carcinogenesis and to evaluate the mechanism. Similar to human breast cancers, a proportion of mammary adenocarcinomas in the WAP-TAg transgenic mouse model demonstrate constitutive Stat5a/b and Stat3 activation. Stat5a activation is linked to mammary epithelial cell survival and differentiation, and proliferation in hematopoetic cell lineages. Breeding WAP-TAg mice to mice carrying germ-line deletions of the Stat5a gene generated mice with reduced levels of Stat5a. Hemizygous loss of the Stat5a allele significantly reduced levels of Stat5a expression without altering mammary gland development or transgene expression levels. In comparison to mice carrying two wild-type Stat5a alleles, hemizygous loss of the Stat5a allele reduced the number of mice with palpable tumors at 7 months of age (67% from 100%, P<0.05), resulted in smaller tumors at 7 months of age (3.8 cm3 from 7.6 cm3, P=0.003), delayed first tumor appearance (208 days from 188 days, P=0.01), and increased the apoptotic index in the adenocarcinomas (4.3+/-0.3 from 1.2+/-0.2, P=0.016). Neither cell proliferation nor differentiation in the cancers was altered. Decreasing Stat5a activation levels could be a therapeutic approach for reducing survival of breast cancer cells.