Abstract
We report here our studies of nuclear staining for the progesterone and estrogen receptors (PRA, PRB, ERα) and cell proliferation (MIB1) in the breast terminal duct lobular unit epithelium of 26 naturally cycling premenopausal women and 30 pregnant women (median 8.1 weeks gestation). Square root transformations of the PRA, PRB and ERα values, and a logarithmic transformation of the MIB1 values, were made to achieve more normal distributions of the values. PRA expression decreased from a mean of 17.8% of epithelial cells in cycling subjects to 6.2% in pregnant subjects (P = 0.013). MIB1 expression increased from 1.7% in cycling subjects to 16.0% in pregnant subjects (P < 0.001). PRB and ERα expression was slightly lower in pregnant subjects but the differences were not statistically significant. Sixteen of the non-pregnant subjects were nulliparous and ten were parous so that we had limited power to detect changes associated with parity. PRA was statistically significantly lower in parous women than in nulliparous women (32.2% in nulliparous women vs. 10.2%; P = 0.014). PRB (23.5 vs. 12.9%), ERα (14.4 vs. 8.6%) and MIB1 (2.2 vs. 1.2%) were also lower in parous women, but the differences were not statistically significant. The marked decreases in PRA in pregnancy and in parous women has also been found in the rat. A reduction in PRA expression may be a useful marker of the reduction in risk with pregnancy and may be of use in evaluating the effect of any chemoprevention regimen aimed at mimicking pregnancy. Short-term changes in PRA expression while the chemoprevention is being administered may be a more useful marker.
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References
Vegeto E, Shahbaz MM, Wen DX, Goldman ME, O’Malley BW, McDonnell DP (1993) Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. Mol Endocrinol 7:1244–1255. doi:10.1210/me.7.10.1244
Kariagina A, Aupperlee MD, Haslam SZ (2007) Progesterone receptor isoforms and proliferation in the rat mammary gland during development. Endocrinology 148:2723–2736. doi:10.1210/en.2006-1493
Aupperlee MD, Smith KT, Kariagina A, Haslam SZ (2005) Progesterone receptor isoforms A and B: temporal and spatial differences in expression during murine mammary gland development. Endocrinology 146:3577–3588. doi:10.1210/en.2005-0346
Russo J, Russo IH (1996) Experimentally induced mammary tumors in rats. Breast Cancer Res Treat 39:7–20. doi:10.1007/BF01806074
Russo IH, Russo J (1998) Role of hormones in mammary cancer initiation and progression. J Mammary Gland Biol Neoplasia 3:49–61. doi:10.1023/A:1018770218022
Taylor CR, Shi SR, Chen C, Young L, Yang C, Cote RJ (1996) Comparative study of antigen retrieval heating methods: microwave, microwave and pressure cooker, autoclave, and steamer. Biotech Histochem 71:263–270. doi:10.3109/10520299609117171
Kumar SR, Singh J, Xia G, Krasnoperov V, Hassanieh L, Ley EJ, Scehnet J, Kumar NG, Hawes D, Press MF (2006) Receptor tyrosine kinase EphB4 is a survival factor in breast cancer. Am J Pathol 169:279–293. doi:10.2353/ajpath.2006.050889
Shoker BS, Jarvis C, Sibson DR, Walker C, Sloane JP (1999) Oestrogen receptor expression in the normal and pre-cancerous breast. J Pathol 188:237–244. doi:10.1002/(SICI)1096-9896(199907)188:3<237::AID-PATH343>3.0.CO;2-8
Collaborative Group on Hormonal Factors in Breast Cancer (2004) Breast cancer and abortion: collaborative reanalysis of data from 53 epidemiological studies, including 83,000 with breast cancer from 16 countries. Lancet 363:1007–1016. doi:10.1016/S0140-6736(04)15835-2
Mote PA, Bartow S, Tran N, Clarke CL (2002) Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Res Treat 72:163–172. doi:10.1023/A:1014820500738
Longacre TA, Bartow SA (1986) A correlative morphologic study of human breast and endometrium in the menstrual cycle. Am J Surg Pathol 10:382–393. doi:10.1097/00000478-198606000-00003
Speirs V, Skliris GP, Burdall SE, Carder PJ (2002) Distinct expression patterns of ER alpha and ER beta in normal human mammary gland. J Clin Pathol 55:371–374
Couse JF, Korach KS (1999) Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 20:358–417. doi:10.1210/er.20.3.358
Petersen OW, Hoyer PE, van Deurs B (1987) Frequency and distribution of estrogen receptor-positive cells in normal, nonlactating human breast tissue. Cancer Res 47:5748–5751
Clarke RB, Howell A, Potten CS, Anderson E (1997) Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res 57:4987–4991
Bartow SA (1998) Use of the autopsy to study ontogeny and expression of the estrogen receptor gene in human breast. J Mammary Gland Biol Neoplasia 3:37–48. doi:10.1023/A:1026641401184
Jacquemier JD, Hassoun J, Torrente M, Martin P-M (1990) Distribution of estrogen and progesterone receptors in healthy tissue adjacent to breast lesions at various stages-Immunohistochemical study of 107 cases. Breast Cancer Res Treat 15:109–117. doi:10.1007/BF01810783
Williams G, Anderson E, Howell A, Watson R, Coyne J, Roberts SA, Potten CS (1991) Oral contraceptive (OCP) use increases proliferation and decreases oestrogen receptor content of epithelial cells in the normal human breast. Int J Cancer 48:206–210. doi:10.1002/ijc.2910480209
Battersby S, Robertson BJ, Anderson TJ, King RJB, McPherson K (1992) Influence of menstrual cycle, parity and oral contraceptive use on steroid hormone receptors in normal breast. Br J Cancer 65:601–607
Söderqvist G, von Schoultz B, Tani E, Skoog L (1993) Estrogen and progesterone receptor content in breast epithelial cells from healthy women during the menstrual cycle. Am J Obstet Gynecol 168:874–879
Russo J, Ao X, Grill C, Russo IH (1999) Pattern of distribution of cells positive for estrogen receptor alpha and progesterone receptor in relation to proliferating cells in the mammary gland. Breast Cancer Res Treat 53:217–227. doi:10.1023/A:1006186719322
Lee S, Mohsin SK, Mao S, Hilsenbeck SG, Medina D, Allred DC (2006) Hormones, receptors, and growth in hyperplastic enlarged lobular units: early potential precursors of breast cancer. Breast Cancer Res 8:R6. doi:10.1186/bcr1367
Battersby S, Anderson TJ (1988) Proliferative and secretory activity in the pregnant and lactating human breast. Virchows Archiv A Pathol Anat 413:189–196
Suzuki R, Atherton AJ, O’Hare MJ, Entwistle A, Lakhani SR, Clarke C (2000) Proliferation and differentiation in the human breast during pregnancy. Differentiation 66:106–115. doi:10.1046/j.1432-0436.2000.660205.x
Olsson H, Jernström H, Alm P, Kreipe H, Ingvar C, Jönsson PE, Rydén S (1996) Proliferation of the breast epithelium in relation to menstrual cycle phase, hormonal use, and reproductive factors. Breast Cancer Res Treat 40:187–196. doi:10.1007/BF01806214
Longacre TA, Bartow SA (1986) A correlative morphologic study of human breast and endometrium in the menstrual cycle. Am J Surg Pathol 10:382–393. doi:10.1097/00000478-198606000-00003
Anderson TJ, Battersby S, King RJB, McPherson K, Going JJ (1989) Oral contraceptive use influences resting breast proliferation. Hum Pathol 20:1139–1144. doi:10.1016/0046-8177(89)90049-X
Williams G, Anderson E, Howell A, Watson R, Coyne J, Roberts SA, Potten CS (1991) Oral contraceptive (OCP) use increases proliferation and decreases oestrogen receptor content of epithelial cells in the normal human breast. Int J Cancer 48:206–210. doi:10.1002/ijc.2910480209
Feuerhake F, Sigg W, Höfter EA, Unterberger P, Welsch U (2003) Cell proliferation, apoptosis, and expression of Bcl-2 and Bax in non-lactating human breast epithelium in relation to the menstrual cycle and reproductive history. Breast Cancer Res Treat 77:37–48. doi:10.1023/A:1021119830269
Joshi K, Smith JA, Perusinghe N, Monoghan P (1986) Cell proliferation in the human mammary epithelium. Am J Pathol 124:199–206
Mote PA, Leary JA, Avery KA, Sandelin K, Chenevix-Trench G, kConfab Investigators, Kirk JA, Clarke CL (2004) Germ-line mutations in BRCA1 or BRCA2 in the normal breast are associated with altered expression of estrogen-responsive proteins and the predominance of progesterone receptor A. Genes Chromosomes Cancer 39:236–248. doi:10.1002/gcc.10321
Jacobsen BM, Richer JK, Sartorius CA, Horwitz KB (2003) Expression profiling of human breast cancers and gene regulation by progesterone receptors. J Mammary Gland Biol Neoplasia 8:257–268. doi:10.1023/B:JOMG.0000010028.48159.84
Shyamala G, Yang X, Silberstein G, Barcellos-Hoff MH, Dale E (1998) Transgenic mice carrying an imbalance in the native ratio of A to B forms of progesterone receptor exhibit developmental abnormalities in mammary glands. Proc Natl Acad Sci USA 95:696–701. doi:10.1073/pnas.95.2.696
Graham JD, Yeates C, Balleine RL, Harvey SS, Milliken JS, Bilous AM, Clarke CL (1995) Characterization of progesterone receptor A and B expression in human breast cancer. Cancer Res 55:5063–5068
Acknowledgments
We wish to express our sincerest gratitude to the women who agreed to be part of these studies. We also wish to express our thanks to Ms. Peggy Wan and Ms. A. Rebecca Anderson for extensive help with the management of the study and the statistical analysis. Drs. Christine Clarke and Patricia Mote provided very valuable advice on certain aspects of immunohistochemistry and pointed us to the best antibody for detection of PRB; we are most grateful for this help. This work was supported by a Department of Defense Congressionally Directed Breast Cancer Research Program Grant BC 044808, by the USC/Norris Comprehensive Cancer Center Core Grant P30 CA14089, funds from the endowment established by Flora L. Thornton for the Chair of Preventive Medicine at the Keck School of Medicine of USC and an anonymous donor grant to DT. The funding sources had no role in this report. Disclosure statement: The authors declare that they have nothing to disclose.
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DeShawn Taylor, Celeste Leigh Pearce, Linda Hovanessian-Larsen, Susan Downey are to be considered joint first authors of this report based on their pivotal contributions to the studies reported here.
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Taylor, D., Pearce, C.L., Hovanessian-Larsen, L. et al. Progesterone and estrogen receptors in pregnant and premenopausal non-pregnant normal human breast. Breast Cancer Res Treat 118, 161–168 (2009). https://doi.org/10.1007/s10549-009-0322-4
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DOI: https://doi.org/10.1007/s10549-009-0322-4