Abstract
Preliminary evidence has associated testosterone and prostate-specific antigen (PSA) with breast cancer. Our objective was to determine whether a) testosterone levels in nipple aspirate fluid (NAF), serum, or breast tissue are associated with breast cancer; b) testosterone levels in serum are associated with levels in NAF; c) PSA in NAF, serum, or breast tissue is associated with breast cancer; and d) serum PSA is associated with NAF PSA levels. We obtained 342 NAF specimens from 171 women by means of a modified breast pump. Additionally, we collected 201 blood samples from 99 women and 51 tissue samples from 41 subjects who underwent surgical resection for suspected disease. Women currently using birth control pills or hormone replacement therapy were excluded from the study. Controlling for age and menopausal status, serum testosterone was significantly increased in women with breast cancer (p = 0.002). NAF and serum testosterone levels were not associated. Neither NAF nor tissue testosterone was associated with breast cancer. Controlling for menopausal status and age, NAF PSA was significantly decreased in women with breast cancer (p < 0.001). We did not find serum PSA to be associated with breast cancer, although we found an indication that, in postmenopausal women, its levels were lower in women with cancer. Serum PSA was associated with NAF PSA in postmenopausal women (p < 0.001). PSA levels in cancerous tissue were significantly lower than in benign breast specimens from subjects without cancer (p = 0.011), whereas levels of PSA in histologically benign specimens from subjects with cancer were intermediate. Our results suggest that serum testosterone is increased and NAF PSA is decreased in women with breast cancer, with PSA expression being higher in normal than in cancerous breast tissues. NAF and serum PSA levels in postmenopausal women are correlated, suggesting that as laboratory assessment of PSA becomes more sensitive, serum PSA may become useful in identifying women with breast cancer.
Full Text
The Full Text of this article is available as a PDF (1.6 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Armbruster D. A. Prostate-specific antigen: biochemistry, analytical methods, and clinical application. Clin Chem. 1993 Feb;39(2):181–195. [PubMed] [Google Scholar]
- Berrino F., Muti P., Micheli A., Bolelli G., Krogh V., Sciajno R., Pisani P., Panico S., Secreto G. Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst. 1996 Mar 6;88(5):291–296. doi: 10.1093/jnci/88.5.291. [DOI] [PubMed] [Google Scholar]
- Black M. H., Diamandis E. P. The diagnostic and prognostic utility of prostate-specific antigen for diseases of the breast. Breast Cancer Res Treat. 2000 Jan;59(1):1–14. doi: 10.1023/a:1006380306781. [DOI] [PubMed] [Google Scholar]
- Black M. H., Giai M., Ponzone R., Sismondi P., Yu H., Diamandis E. P. Serum total and free prostate-specific antigen for breast cancer diagnosis in women. Clin Cancer Res. 2000 Feb;6(2):467–473. [PubMed] [Google Scholar]
- Botti C., Pescatore B., Mottolese M., Sciarretta F., Greco C., Di Filippo F., Gandolfo G. M., Cavaliere F., Bovani R., Varanese A. Incidence of chromosomes 1 and 17 aneusomy in breast cancer and adjacent tissue: an interphase cytogenetic study. J Am Coll Surg. 2000 May;190(5):530–539. doi: 10.1016/s1072-7515(00)00252-0. [DOI] [PubMed] [Google Scholar]
- Darson M. F., Pacelli A., Roche P., Rittenhouse H. G., Wolfert R. L., Young C. Y., Klee G. G., Tindall D. J., Bostwick D. G. Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker. Urology. 1997 Jun;49(6):857–862. doi: 10.1016/s0090-4295(97)00108-8. [DOI] [PubMed] [Google Scholar]
- Diamandis E. P., Yu H. New biological functions of prostate-specific antigen? J Clin Endocrinol Metab. 1995 May;80(5):1515–1517. doi: 10.1210/jcem.80.5.7538144. [DOI] [PubMed] [Google Scholar]
- Diamandis E. P., Yu H. Nonprostatic sources of prostate-specific antigen. Urol Clin North Am. 1997 May;24(2):275–282. doi: 10.1016/s0094-0143(05)70373-6. [DOI] [PubMed] [Google Scholar]
- Dorgan J. F., Longcope C., Stanczyk F. Z., Stephenson H. E., Jr, Hoover R. N. Re: Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 1999 Feb 17;91(4):380–381. doi: 10.1093/jnci/91.4.380. [DOI] [PubMed] [Google Scholar]
- Dorgan J. F., Longcope C., Stephenson H. E., Jr, Falk R. T., Miller R., Franz C., Kahle L., Campbell W. S., Tangrea J. A., Schatzkin A. Serum sex hormone levels are related to breast cancer risk in postmenopausal women. Environ Health Perspect. 1997 Apr;105 (Suppl 3):583–585. doi: 10.1289/ehp.97105s3583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ferguson R. A., Yu H., Kalyvas M., Zammit S., Diamandis E. P. Ultrasensitive detection of prostate-specific antigen by a time-resolved immunofluorometric assay and the Immulite immunochemiluminescent third-generation assay: potential applications in prostate and breast cancers. Clin Chem. 1996 May;42(5):675–684. [PubMed] [Google Scholar]
- Gammon M. D., Hibshoosh H., Terry M. B., Bose S., Schoenberg J. B., Brinton L. A., Bernstein J. L., Thompson W. D. Cigarette smoking and other risk factors in relation to p53 expression in breast cancer among young women. Cancer Epidemiol Biomarkers Prev. 1999 Mar;8(3):255–263. [PubMed] [Google Scholar]
- Grattarola R., Secreto G., Recchione C. Androgens in breast cancer. III. Breast cancer recurrences years after mastectomy and increased androgenic activity. Am J Obstet Gynecol. 1975 Jan 15;121(2):169–172. [PubMed] [Google Scholar]
- Grattarola R., Secreto G., Recchione C., Castellini W. Androgens in breast cancer. II. Endometrial adenocarcinoma and breast cancer in married postmenopausal women. Am J Obstet Gynecol. 1974 Jan 15;118(2):173–178. [PubMed] [Google Scholar]
- Hankinson S. E., Willett W. C., Manson J. E., Colditz G. A., Hunter D. J., Spiegelman D., Barbieri R. L., Speizer F. E. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 1998 Sep 2;90(17):1292–1299. doi: 10.1093/jnci/90.17.1292. [DOI] [PubMed] [Google Scholar]
- Hassan H. I., Walker R. A. Decreased apoptosis in non-involved tissue from cancer-containing breasts. J Pathol. 1998 Mar;184(3):258–264. doi: 10.1002/(SICI)1096-9896(199803)184:3<258::AID-PATH999>3.0.CO;2-6. [DOI] [PubMed] [Google Scholar]
- Kandel R., Li S. Q., Ozcelik H., Rohan T. p53 protein accumulation and mutations in normal and benign breast tissue. Int J Cancer. 2000 Jul 1;87(1):73–78. doi: 10.1002/1097-0215(20000701)87:1<73::aid-ijc11>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
- Lichtenstein P., Holm N. V., Verkasalo P. K., Iliadou A., Kaprio J., Koskenvuo M., Pukkala E., Skytthe A., Hemminki K. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000 Jul 13;343(2):78–85. doi: 10.1056/NEJM200007133430201. [DOI] [PubMed] [Google Scholar]
- Magklara A., Grass L., Diamandis E. P. Differential steroid hormone regulation of human glandular kallikrein (hK2) and prostate-specific antigen (PSA) in breast cancer cell lines. Breast Cancer Res Treat. 2000 Feb;59(3):263–270. doi: 10.1023/a:1006304518750. [DOI] [PubMed] [Google Scholar]
- Mai K. T. Morphological evidence for field effect as a mechanism for tumour spread in mammary Paget's disease. Histopathology. 1999 Dec;35(6):567–576. doi: 10.1046/j.1365-2559.1999.00788.x. [DOI] [PubMed] [Google Scholar]
- Malejka-Giganti D., Niehans G. A., Reichert M. A., Bennett K. K., Bliss R. L. Potent carcinogenicity of 2,7-dinitrofluorene, an environmental pollutant, for the mammary gland of female Sprague-Dawley rats. Carcinogenesis. 1999 Oct;20(10):2017–2023. doi: 10.1093/carcin/20.10.2017. [DOI] [PubMed] [Google Scholar]
- Oesterling J. E. Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J Urol. 1991 May;145(5):907–923. doi: 10.1016/s0022-5347(17)38491-4. [DOI] [PubMed] [Google Scholar]
- Pardridge W. M. Transport of protein-bound hormones into tissues in vivo. Endocr Rev. 1981 Winter;2(1):103–123. doi: 10.1210/edrv-2-1-103. [DOI] [PubMed] [Google Scholar]
- Rose D. P., Berke B., Cohen L. A., Lahti H. A comparison of serum and breast duct fluid-immunoassayable prolactin and growth hormone with bioassayable lactogenic hormones in healthy women and patients with cystic breast disease. Cancer. 1987 Dec 1;60(11):2761–2765. doi: 10.1002/1097-0142(19871201)60:11<2761::aid-cncr2820601128>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
- Sauter E. R., Daly M., Linahan K., Ehya H., Engstrom P. F., Bonney G., Ross E. A., Yu H., Diamandis E. Prostate-specific antigen levels in nipple aspirate fluid correlate with breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1996 Dec;5(12):967–970. [PubMed] [Google Scholar]
- Sauter E. R., Ehya H., Babb J., Diamandis E., Daly M., Klein-Szanto A., Sigurdson E., Hoffman J., Malick J., Engstrom P. F. Biological markers of risk in nipple aspirate fluid are associated with residual cancer and tumour size. Br J Cancer. 1999 Dec;81(7):1222–1227. doi: 10.1038/sj.bjc.6690832. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Secreto G., Fariselli G., Bandieramonte G., Recchione C., Dati V., Di Pietro S. Androgen excretion in women with a family history of breast cancer or with epithelial hyperplasia or cancer of the breast. Eur J Cancer Clin Oncol. 1983 Jan;19(1):5–10. doi: 10.1016/0277-5379(83)90389-9. [DOI] [PubMed] [Google Scholar]
- Secreto G., Recchione C., Cavalleri A., Miraglia M., Dati V. Circulating levels of testosterone, 17 beta-oestradiol, luteinising hormone and prolactin in postmenopausal breast cancer patients. Br J Cancer. 1983 Feb;47(2):269–275. doi: 10.1038/bjc.1983.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Secreto G., Recchione C., Fariselli G., Di Pietro S. High testosterone and low progesterone circulating levels in premenopausal patients with hyperplasia and cancer of the breast. Cancer Res. 1984 Feb;44(2):841–844. [PubMed] [Google Scholar]
- Stark A., Hulka B. S., Joens S., Novotny D., Thor A. D., Wold L. E., Schell M. J., Melton L. J., 3rd, Liu E. T., Conway K. HER-2/neu amplification in benign breast disease and the risk of subsequent breast cancer. J Clin Oncol. 2000 Jan;18(2):267–274. doi: 10.1200/JCO.2000.18.2.267. [DOI] [PubMed] [Google Scholar]
- Thomas H. V., Key T. J., Allen D. S., Moore J. W., Dowsett M., Fentiman I. S., Wang D. Y. A prospective study of endogenous serum hormone concentrations and breast cancer risk in premenopausal women on the island of Guernsey. Br J Cancer. 1997;75(7):1075–1079. doi: 10.1038/bjc.1997.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yu H., Diamandis E. P., Levesque M., Giai M., Roagna R., Ponzone R., Sismondi P., Monne M., Croce C. M. Prostate specific antigen in breast cancer, benign breast disease and normal breast tissue. Breast Cancer Res Treat. 1996;40(2):171–178. doi: 10.1007/BF01806212. [DOI] [PubMed] [Google Scholar]
- Yu H., Diamandis E. P., Zarghami N., Grass L. Induction of prostate specific antigen production by steroids and tamoxifen in breast cancer cell lines. Breast Cancer Res Treat. 1994;32(3):291–300. doi: 10.1007/BF00666006. [DOI] [PubMed] [Google Scholar]
- Zarghami N., D'Costa M., Tsuyuki D., Asa S. L., Diamandis E. P. Expression of the prostate specific antigen gene by lung tissue. Clin Cancer Res. 1997 Jul;3(7):1201–1206. [PubMed] [Google Scholar]
- Zarghami N., Grass L., Diamandis E. P. Steroid hormone regulation of prostate-specific antigen gene expression in breast cancer. Br J Cancer. 1997;75(4):579–588. doi: 10.1038/bjc.1997.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zeleniuch-Jacquotte A., Bruning P. F., Bonfrer J. M., Koenig K. L., Shore R. E., Kim M. Y., Pasternack B. S., Toniolo P. Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women. Am J Epidemiol. 1997 Jun 1;145(11):1030–1038. doi: 10.1093/oxfordjournals.aje.a009059. [DOI] [PubMed] [Google Scholar]
- Zhao Y., Verselis S. J., Klar N., Sadowsky N. L., Kaelin C. M., Smith B., Foretova L., Li F. P. Nipple fluid carcinoembryonic antigen and prostate-specific antigen in cancer-bearing and tumor-free breasts. J Clin Oncol. 2001 Mar 1;19(5):1462–1467. doi: 10.1200/JCO.2001.19.5.1462. [DOI] [PubMed] [Google Scholar]