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Aromatase immunoreactivity is increased in mammographically dense regions of the breast

  • Epidemiology
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Abstract

Mammographic breast density (MBD) is one of the strongest risk factors for breast cancer. Unfortunately, the biologic basis underlying this association is unknown. This study compared aromatase expression or immunoreactivity (IR) in core biopsies from mammographically dense versus non-dense regions of the breast to examine whether estrogen synthesis in the breast is associated with MBD and one possible mechanism through which MBD may influence breast cancer. Eligible participants were 40+ years, had a screening mammogram with visible MBD and no prior cancer or current endocrine therapy. Mammograms were used to identify dense and non-dense regions and ultrasound-guided core biopsies were performed to obtain tissue from these regions. Immunostaining for aromatase employed the streptavidin–biotin amplification method and #677 mouse monoclonal antibody. Aromatase IR was scored in terms of extent and intensity of staining for each cell type (stroma, epithelium, adipocytes) on histologic sections. A modified histological H-score provided quantitation of aromatase IR in each cell type and overall. Repeated measure analyses evaluated average differences (βH) in H-score in dense versus non-dense tissue within and across cell types. Forty-nine women with mean age 50 years (range: 40–82), participated. Aromatase IR was increased in dense (vs. non-dense) tissue in both the stroma (βH = 0.58) and epithelium (βH = 0.12) (P < 0.01). Adipocytes from non-dense tissue, however, had a greater IR compared to those from dense tissue (βH = −0.24, P < 0.01). An overall H-score which integrated results from all cell types demonstrated that aromatase IR was twice as great for dense (mean H-score = 0.90, SD = 0.53) versus non-dense (mean H-score = 0.45, SD = 0.39) breast tissue (βH = 0.45; P < 0.001). Overall, aromatase IR was greater for mammographically dense versus non-dense tissue and may partly explain how MBD influences breast cancer.

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References

  1. McCormack VA, Highnam R, Perry N, dos Santos Silva I (2007) Comparison of a new and existing method of mammographic density measurement: intramethod reliability and associations with known risk factors. Cancer Epidemiol Biomarkers Prev 16:1148–1154

    Article  PubMed  Google Scholar 

  2. Martin LJ, Boyd NF (2008) Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence. Breast Cancer Res 10:201

    Article  PubMed  Google Scholar 

  3. Greendale GA, Palla SL, Ursin G, Laughlin GA, Crandall C, Pike MC, Reboussin BA (2005) The association of endogenous sex steroids and sex steroid binding proteins with mammographic density: results from the Postmenopausal Estrogen/Progestin Interventions Mammographic Density Study. Am J Epidemiol 162:826–834

    Article  PubMed  Google Scholar 

  4. Verheus M, Peeters PH, van Noord PA, van der Schouw YT, Grobbee DE, van Gils CH (2007) No relationship between circulating levels of sex steroids and mammographic breast density: the Prospect-EPIC cohort. Breast Cancer Res 9:R53

    Article  PubMed  Google Scholar 

  5. McCormack VA, Dowsett M, Folkerd E, Johnson N, Palles C, Coupland B, Holly JM, Vinnicombe SJ, Perry NM, dos Santos Silva I (2009) Sex steroids, growth factors and mammographic density: a cross-sectional study of UK postmenopausal Caucasian and Afro-Caribbean women. Breast Cancer Res 11:R38

    Article  PubMed  Google Scholar 

  6. Tamimi RM, Byrne C, Colditz GA, Hankinson SE (2007) Endogenous hormone levels, mammographic density, and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst 99:1178–1187

    Article  CAS  PubMed  Google Scholar 

  7. Miller WR, O’Neill J (1987) The importance of local synthesis of estrogen within the breast. Steroids 50:537–548

    Article  CAS  PubMed  Google Scholar 

  8. Dunbier AK, Anderson H, Folkerd E, Ghazoui Z, Smith IE, Ellis MJ, Dowsett M, Neoadjuvant Letrozole Study Group (2009) Expression of estrogen responsive genes in breast cancers correlates with plasma estradiol levels in postmenopausal women. Cancer Res 69:63

    Google Scholar 

  9. Miller WR, Dixon JM, Macfarlane L, Cameron D, Anderson TJ (2003) Pathological features of breast cancer response following neoadjuvant treatment with either letrozole or tamoxifen. Eur J Cancer 39:462–468

    Article  CAS  PubMed  Google Scholar 

  10. Yue W, Wang JP, Hamilton CJ, Demers LM, Santen RJ (1998) In situ aromatization enhances breast tumor estradiol levels and cellular proliferation. Cancer Res 58:927–932

    CAS  PubMed  Google Scholar 

  11. Lipton A, Harvey HA, Demers LM, Hanagan JR, Mulagha MT, Kochak GM, Fitzsimmons S, Sanders SI, Santen RJ (1990) A phase I trial of CGS 16949A. A new aromatase inhibitor. Cancer 65:1279–1285

    Article  CAS  PubMed  Google Scholar 

  12. Brodie A, Lu Q, Long B (1999) Aromatase and its inhibitors. J Steroid Biochem Mol Biol 69:205–210

    Article  CAS  PubMed  Google Scholar 

  13. Morales L, Neven P, Paridaens R (2005) Choosing between an aromatase inhibitor and tamoxifen in the adjuvant setting. Curr Opin Oncol 17:559–565

    Article  CAS  PubMed  Google Scholar 

  14. Santen RJ, Martel J, Hoagland M, Naftolin F, Roa L, Harada N, Hafer L, Zaino R, Santner SJ (1994) Stromal spindle cells contain aromatase in human breast tumors. J Clin Endocrinol Metab 79:627–632

    Article  CAS  PubMed  Google Scholar 

  15. Boyd NF, Martin LJ, Yaffe MJ, Minkin S (2006) Mammographic density: a hormonally responsive risk factor for breast cancer. J Br Menopause Soc 12:186–193

    Article  PubMed  Google Scholar 

  16. Alowami S, Troup S, Al-Haddad S, Kirkpatrick I, Watson PH (2003) Mammographic density is related to stroma and stromal proteoglycan expression. Breast Cancer Res 5:R129–R135

    Article  CAS  PubMed  Google Scholar 

  17. Li T, Sun L, Miller N, Nicklee T, Woo J, Hulse-Smith L, Tsao MS, Khokha R, Martin L, Boyd N (2005) The association of measured breast tissue characteristics with mammographic density and other risk factors for breast cancer. Cancer Epidemiol Biomarkers Prev 14:343–349

    Article  PubMed  Google Scholar 

  18. Hawes D, Downey S, Pearce CL, Bartow S, Wan P, Pike MC, Wu AH (2006) Dense breast stromal tissue shows greatly increased concentration of breast epithelium but no increase in its proliferative activity. Breast Cancer Res 8:R24

    Article  PubMed  Google Scholar 

  19. Stomper PC, Penetrante RB, Edge SB, Arredondo MA, Blumenson LE, Stewart CC (1996) Cellular proliferative activity of mammographic normal dense and fatty tissue determined by DNA S phase percentage. Breast Cancer Res Treat 37:229–236

    Article  CAS  PubMed  Google Scholar 

  20. Khan QJ, Kimler BF, O’Dea AP, Zalles CM, Sharma P, Fabian CJ (2007) Mammographic density does not correlate with Ki-67 expression or cytomorphology in benign breast cells obtained by random periareolar fine needle aspiration from women at high risk for breast cancer. Breast Cancer Res 9:R35

    Article  PubMed  Google Scholar 

  21. Verheus M, Maskarinec G, Erber E, Steude JS, Killeen J, Hernandez BY, Cline JM (2009) Mammographic density and epithelial histopathologic markers. BMC Cancer 9:182

    Article  PubMed  Google Scholar 

  22. Harvey JA, Santen RJ, Petroni GR, Bovbjerg VE, Smolkin ME, Sheriff FS, Russo J (2008) Histologic changes in the breast with menopausal hormone therapy use: correlation with breast density, estrogen receptor, progesterone receptor, and proliferation indices. Menopause 15:67–73

    PubMed  Google Scholar 

  23. Santner SJ, Pauley RJ, Tait L, Kaseta J, Santen RJ (1997) Aromatase activity and expression in breast cancer and benign breast tissue stromal cells. J Clin Endocrinol Metab 82:200–208

    Article  CAS  PubMed  Google Scholar 

  24. Ghosh S, Choudary A, Ghosh S, Musi N, Hu Y, Li R (2009) IKKbeta mediates cell shape-induced aromatase expression and estrogen biosynthesis in adipose stromal cells. Mol Endocrinol 23:662–670

    Article  CAS  PubMed  Google Scholar 

  25. Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Gurates B et al (2005) Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev 57:359–383

    Article  CAS  PubMed  Google Scholar 

  26. Zhou J, Gurates B, Yang S, Sebastian S, Bulun SE (2001) Malignant breast epithelial cells stimulate aromatase expression via promoter II in human adipose fibroblasts: an epithelial-stromal interaction in breast tumors mediated by CCAAT/enhancer binding protein beta. Cancer Res 61:2328–2334

    CAS  PubMed  Google Scholar 

  27. Bulun SE, Price TM, Aitken J, Mahendroo MS, Simpson ER (1993) A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab 77:1622–1628

    Article  CAS  PubMed  Google Scholar 

  28. Bulun SE, Simpson ER (1994) Regulation of aromatase expression in human tissues. Breast Cancer Res Treat 30:19–29

    Article  CAS  PubMed  Google Scholar 

  29. Bulun SE, Sharda G, Rink J, Sharma S, Simpson ER (1996) Distribution of aromatase P450 transcripts and adipose fibroblasts in the human breast. J Clin Endocrinol Metab 81:1273–1277

    Article  CAS  PubMed  Google Scholar 

  30. Liu GJ, Wu YS, Brenin D, Yue W, Aiyar S, Gompel A, Wang JP, Tekmal RR, Santen RJ (2008) Development of a high sensitivity, nested Q-PCR assay for mouse and human aromatase. Breast Cancer Res Treat 111:343–351

    Article  CAS  PubMed  Google Scholar 

  31. Santner SJ, Feil PD, Santen RJ (1984) In situ estrogen production via the estrone sulfatase pathway in breast tumors: relative importance versus the aromatase pathway. J Clin Endocrinol Metab 59:29–33

    Article  CAS  PubMed  Google Scholar 

  32. Suzuki T, Nakata T, Miki Y, Kaneko C, Moriya T, Ishida T, Akinaga S, Hirakawa H, Kimura M, Sasano H (2003) Estrogen sulfotransferase and steroid sulfatase in human breast carcinoma. Cancer Res 63:2762–2770

    CAS  PubMed  Google Scholar 

  33. Miki Y, Nakata T, Suzuki T, Darnel AD, Moriya T, Kaneko C, Hidaka K, Shiotsu Y, Kusaka H, Sasano H (2002) Systemic distribution of steroid sulfatase and estrogen sulfotransferase in human adult and fetal tissues. J Clin Endocrinol Metab 87:5760–5768

    Article  CAS  PubMed  Google Scholar 

  34. Vachon CM, Ingle JN, Suman VJ, Scott CG, Gottardt H, Olson JE, Goss PE (2007) Pilot study of the impact of letrozole vs. placebo on breast density in women completing 5 years of tamoxifen. Breast 16:204–210

    Article  CAS  PubMed  Google Scholar 

  35. Cuzick J, Warwick J, Pinney E, Warren RM, Duffy SW (2004) Tamoxifen and breast density in women at increased risk of breast cancer. J Natl Cancer Inst 96:621–628

    Article  CAS  PubMed  Google Scholar 

  36. Cigler T, Tu D, Yaffe MJ, Findlay B, Verma S, Johnston D, Richardson H, Hu H, Qi S, Goss PE (2009) A randomized, placebo-controlled trial (NCIC CTG MAP1) examining the effects of letrozole on mammographic breast density and other end organs in postmenopausal women. Breast Cancer Res Treat. 2009 Dec 6 [Epub ahead of print]

  37. Fabian CJ, Kimler BF, Zalles CM, Khan QJ, Mayo MS, Phillips TA, Simonsen M, Metheny T, Petroff BK (2007) Reduction in proliferation with six months of letrozole in women on hormone replacement therapy. Breast Cancer Res Treat 106:75–84

    Article  CAS  PubMed  Google Scholar 

  38. Mousa NA, Crystal P, Wolfman WL, Bedaiwy MA, Casper RF (2008) Aromatase inhibitors and mammographic breast density in postmenopausal women receiving hormone therapy. Menopause 15:875–884

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the participants in this study, who provided samples for investigations of the determinants of breast density. This study was financially supported by the Mayo Clinic Breast SPORE, NIH CA116201; NIH K12 RR24151 for the KL2 Clinical and Translational Science Award-Mentored Career Development Program; and Friends for an Earlier Breast Cancer Test.

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Authors and Affiliations

  1. Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Celine M. Vachon, Karthik Ghosh, Kathleen R. Brandt, David A. Watson, Carol Reynolds, Wilma L. Lingle, Christopher G. Scott, V. Shane Pankratz & James N. Ingle

  2. Tohoku University School of Medicine, Sendai, Tohoku, Japan

    Hironobu Sasano

  3. Massachusetts General Hospital, Boston, MA, USA

    Paul E. Goss

  4. University of Virginia Health System, Charlottesville, VA, USA

    Sarah E. Aiyar & Richard J. Santen

  5. University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Rong Li

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  1. Celine M. Vachon
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  2. Hironobu Sasano
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Correspondence to Celine M. Vachon.

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Vachon, C.M., Sasano, H., Ghosh, K. et al. Aromatase immunoreactivity is increased in mammographically dense regions of the breast. Breast Cancer Res Treat 125, 243–252 (2011). https://doi.org/10.1007/s10549-010-0944-6

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  • DOI: https://doi.org/10.1007/s10549-010-0944-6

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