Prostate-specific antigen (PSA) is produced by the female breast. Prior in vitro evidence suggests that PSA expression in breast epithelial cells is regulated by androgens and progestins but not estrogens. The purpose of this study was to determine whether (a) PSA expression in breast nipple aspirate fluid (NAF) and in serum is influenced by progesterone (PG); (b) the ability to obtain NAF decreases with repeated breast aspirations; and (c) PSA in NAF correlates with abnormal NAF cytology. Eight pre- and three postmenopausal women with no breast cancer risk factors were enrolled in a pilot study and had NAF and serum collected every 3-4 days for a month to evaluate the influence of serum PG, luteinizing hormone, estradiol, and follicle-stimulating hormone on PSA in serum and in NAF. NAF was obtained in 99% (112 of 113) of aspiration visits. Median, mean, and peak NAF but not serum PSA levels were higher in pre- than in postmenopausal subjects. NAF PSA levels were associated with the rise or peak in serum PG in seven of eight premenopausal women (seven of seven with a PG surge) and in zero of three postmenopausal women. Considering all 11 women, there was an association between NAF PSA and PG (P = 0.005) but not luteinizing hormone, estradiol, or follicle-stimulating hormone. NAF volume did not significantly change over time. Atypical hyperplasia (9%) and hyperplasia without atypia (36%) were identified in the NAF of a subset of the subjects. Median, mean, and peak levels of NAF PSA (P = 0.05, 0.05, and 0.10, respectively) were higher in subjects with normal versus hyperplastic cytology. PSA production in the breast increases in association with PG. With aspiration every 3-4 days, NAF volume does not significantly decrease over time. NAF cytology and PSA levels in NAF may help identify women at increased breast cancer risk. Changes in biomarkers of breast cancer risk in NAF (including PSA and cytology) may predate mammographic abnormalities. NAF may, therefore, be useful as a breast cancer screening tool for young women who are not recommended to undergo mammography and as an adjunct to screen women who have mammograms performed.

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