Skip to main content

Advertisement

Log in

Image-guided sampling reveals increased stroma and lower glandular complexity in mammographically dense breast tissue

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Mammographic density (MD) adjusted for age and body mass index (BMI) is a strong heritable breast cancer risk factor; however, its biological basis remains elusive. Previous studies assessed MD-associated histology using random sampling approaches, despite evidence that high and low MD areas exist within a breast and are negatively correlated with respect to one another. We have used an image-guided approach to sample high and low MD tissues from within individual breasts to examine the relationship between histology and degree of MD. Image-guided sampling was performed using two different methodologies on mastectomy tissues (n = 12): (1) sampling of high and low MD regions within a slice guided by bright (high MD) and dark (low MD) areas in a slice X-ray film; (2) sampling of high and low MD regions within a whole breast using a stereotactically guided vacuum-assisted core biopsy technique. Pairwise analysis accounting for potential confounders (i.e. age, BMI, menopausal status, etc.) provides appropriate power for analysis despite the small sample size. High MD tissues had higher stromal (P = 0.002) and lower fat (P = 0.002) compositions, but no evidence of difference in glandular areas (P = 0.084) compared to low MD tissues from the same breast. High MD regions had higher relative gland counts (P = 0.023), and a preponderance of Type I lobules in high MD compared to low MD regions was observed in 58% of subjects (n = 7), but did not achieve significance. These findings clarify the histologic nature of high MD tissue and support hypotheses regarding the biophysical impact of dense connective tissue on mammary malignancy. They also provide important terms of reference for ongoing analyses of the underlying genetics of MD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. 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  PubMed  CAS  Google Scholar 

  2. Bissell MJ, Hall HG, Parry G (1982) How does the extracellular matrix direct gene expression? J Theor Biol 99:31–68

    Article  PubMed  CAS  Google Scholar 

  3. Bland KI, Kuhns JG, Buchanan JB, Dwyer PA, Heuser LF, O’Connor CA, Gray LA Sr, Polk HC Jr (1982) A clinicopathologic correlation of mammographic parenchymal patterns and associated risk factors for human mammary carcinoma. Ann Surg 195:582–594

    Article  PubMed  CAS  Google Scholar 

  4. Boyd NF, Lockwood GA, Byng JW, Tritchler DL, Yaffe MJ (1998) Mammographic densities and breast cancer risk. Cancer Epidemiol Biomarkers Prev 7:1133–1144

    PubMed  CAS  Google Scholar 

  5. Boyd NF, Dite GS, Stone J, Gunasekara A, English DR, McCredie MR, Giles GG, Tritchler D, Chiarelli A, Yaffe MJ, Hopper JL (2002) Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med 347:886–894

    Article  PubMed  Google Scholar 

  6. Boyd NF, Martin LJ, Rommens JM, Paterson AD, Minkin S, Yaffe MJ, Stone J, Hopper JL (2009) Mammographic density: a heritable risk factor for breast cancer. Methods Mol Biol (Clifton, NJ) 472:343–360

    Article  Google Scholar 

  7. Bright RA, Morrison AS, Brisson J, Burstein NA, Sadowsky NS, Kopans DB, Meyer JE (1988) Relationship between mammographic and histologic features of breast tissue in women with benign biopsies. Cancer 61:266–271

    Article  PubMed  CAS  Google Scholar 

  8. Chen J, Diacovo TG, Grenache DG, Santoro SA, Zutter MM (2002) The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 161:337–344

    Article  PubMed  CAS  Google Scholar 

  9. Chen Z, Wu AH, Gauderman WJ, Bernstein L, Ma H, Pike MC, Ursin G (2004) Does mammographic density reflect ethnic differences in breast cancer incidence rates? Am J Epidemiol 159:140–147

    Article  PubMed  Google Scholar 

  10. Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R, Wareham N, Ahmed S, Healey CS, Bowman R, Meyer KB, Haiman CA, Kolonel LK, Henderson BE, Le Marchand L, Brennan P, Sangrajrang S, Gaborieau V, Odefrey F, Shen CY, Wu PE, Wang HC, Eccles D, Evans DG, Peto J, Fletcher O, Johnson N, Seal S, Stratton MR, Rahman N, Chenevix-Trench G, Bojesen SE, Nordestgaard BG, Axelsson CK, Garcia-Closas M, Brinton L, Chanock S, Lissowska J, Peplonska B, Nevanlinna H, Fagerholm R, Eerola H, Kang D, Yoo KY, Noh DY, Ahn SH, Hunter DJ, Hankinson SE, Cox DG, Hall P, Wedren S, Liu J, Low YL, Bogdanova N, Schurmann P, Dork T, Tollenaar RA, Jacobi CE, Devilee P, Klijn JG, Sigurdson AJ, Doody MM, Alexander BH, Zhang J, Cox A, Brock IW, MacPherson G, Reed MW, Couch FJ, Goode EL, Olson JE, Meijers-Heijboer H, van den Ouweland A, Uitterlinden A, Rivadeneira F, Milne RL, Ribas G, Gonzalez-Neira A, Benitez J, Hopper JL, McCredie M, Southey M, Giles GG, Schroen C, Justenhoven C, Brauch H, Hamann U, Ko YD, Spurdle AB, Beesley J, Chen X, Mannermaa A, Kosma VM, Kataja V, Hartikainen J, Day NE et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–1093

    Article  PubMed  CAS  Google Scholar 

  11. Fata JE, Werb Z, Bissell MJ (2004) Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast Cancer Res 6:1–11

    PubMed  CAS  Google Scholar 

  12. Fisher ER, Palekar A, Kim WS, Redmond C (1978) The histopathology of mammographic patterns. Am J Clin Pathol 69:421–426

    PubMed  CAS  Google Scholar 

  13. Ghajar CM, Bissell MJ (2008) Extracellular matrix control of mammary gland morphogenesis and tumorigenesis: insights from imaging. Histochem Cell Biol 130:1105–1118

    Article  PubMed  CAS  Google Scholar 

  14. Ghosh K, Hartmann LC, Reynolds C, Visscher DW, Brandt KR, Vierkant RA, Scott CG, Radisky DC, Sellers TA, Pankratz VS, Vachon CM (2010) Association between mammographic density and age-related lobular involution of the breast. J Clin Oncol 28:2207–2212

    Article  PubMed  Google Scholar 

  15. Gierach GL, Loud JT, Chow CK, Prindiville SA, Eng-Wong J, Soballe PW, Giambartolomei C, Mai PL, Galbo CE, Nichols K, Calzone KA, Vachon C, Gail MH, Greene MH (2010) Mammographic density does not differ between unaffected BRCA1/2 mutation carriers and women at low-to-average risk of breast cancer. Breast Cancer Res Treat 123:245–255

    Article  PubMed  Google Scholar 

  16. Guo YP, Martin LJ, Hanna W, Banerjee D, Miller N, Fishell E, Khokha R, Boyd NF (2001) Growth factors and stromal matrix proteins associated with mammographic densities. Cancer Epidemiol Biomarkers Prev 10:243–248

    PubMed  CAS  Google Scholar 

  17. Harmes DC, DiRenzo J (2009) Cellular quiescence in mammary stem cells and breast tumor stem cells: got testable hypotheses? J Mammary Gland Biolo Neoplasia 14:19–27

    Article  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. Kass L, Erler JT, Dembo M, Weaver VM (2007) Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis. Int J Biochem Cell Biol 39:1987–1994

    Article  PubMed  CAS  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. Kimata K, Sakakura T, Inaguma Y, Kato M, Nishizuka Y (1985) Participation of two different mesenchymes in the developing mouse mammary gland: synthesis of basement membrane components by fat pad precursor cells. J Embryol Exp Morphol 89:243–257

    PubMed  CAS  Google Scholar 

  22. 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 

  23. Maskarinec G, Nagata C, Shimizu H, Kashiki Y (2002) Comparison of mammographic densities and their determinants in women from Japan and Hawaii. Int J Cancer 102:29–33

    Article  PubMed  CAS  Google Scholar 

  24. McCormack VA, dos Santos Silva I (2006) Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15:1159–1169

    Article  PubMed  Google Scholar 

  25. Milanese TR, Hartmann LC, Sellers TA, Frost MH, Vierkant RA, Maloney SD, Pankratz VS, Degnim AC, Vachon CM, Reynolds CA, Thompson RA, Melton LJ 3rd, Goode EL, Visscher DW (2006) Age-related lobular involution and risk of breast cancer. J Natl Cancer Inst 98:1600–1607

    Article  PubMed  Google Scholar 

  26. Mitchell G, Antoniou AC, Warren R, Peock S, Brown J, Davies R, Mattison J, Cook M, Warsi I, Evans DG, Eccles D, Douglas F, Paterson J, Hodgson S, Izatt L, Cole T, Burgess L, Eeles R, Easton DF (2006) Mammographic density and breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Res 66:1866–1872

    Article  PubMed  CAS  Google Scholar 

  27. Naylor MJ, Ormandy CJ (2002) Mouse strain-specific patterns of mammary epithelial ductal side branching are elicited by stromal factors. Dev Dyn 225:100–105

    Article  PubMed  CAS  Google Scholar 

  28. Odefrey F, Stone J, Gurrin LC, Byrnes GB, Apicella C, Dite GS, Cawson JN, Giles GG, Treloar SA, English DR, Hopper JL, Southey MC (2010) Common genetic variants associated with breast cancer and mammographic density measures that predict disease. Cancer Res 70:1449–1458

    Article  PubMed  CAS  Google Scholar 

  29. Paszek MJ, Weaver VM (2004) The tension mounts: mechanics meets morphogenesis and malignancy. J Mammary Gland Biol Neoplasia 9:325–342

    Article  PubMed  Google Scholar 

  30. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, Reinhart-King CA, Margulies SS, Dembo M, Boettiger D, Hammer DA, Weaver VM (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254

    Article  PubMed  CAS  Google Scholar 

  31. Provenzano PP, Inman DR, Eliceiri KW, Keely PJ (2009) Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene 28:4326–4343

    Article  PubMed  CAS  Google Scholar 

  32. Radisky DC, Hirai Y, Bissell MJ (2003) Delivering the message: epimorphin and mammary epithelial morphogenesis. Trends Cell Biol 13:426–434

    Article  PubMed  CAS  Google Scholar 

  33. Roduit N (2008) JMicroVision: Image analysis toolbox for measuring and quantifying components of high-definition images. Version 1.2.7. http://www.jmicrovision.com

  34. Russo IH, Russo J (1996) Mammary gland neoplasia in long-term rodent studies. Environ Health Perspect 104:938–967

    Article  PubMed  CAS  Google Scholar 

  35. Russo J, Russo IH (1997) Toward a unified concept of mammary carcinogenesis. Prog Clin Biol Res 396:1–16

    PubMed  CAS  Google Scholar 

  36. Russo J, Russo IH (2004) Development of the human breast. Maturitas 49:2–15

    Article  PubMed  CAS  Google Scholar 

  37. Russo J, Reina D, Frederick J, Russo IH (1988) Expression of phenotypical changes by human breast epithelial cells treated with carcinogens in vitro. Cancer Res 48:2837–2857

    PubMed  CAS  Google Scholar 

  38. Russo J, Rivera R, Russo IH (1992) Influence of age and parity on the development of the human breast. Breast Cancer Res Treat 23:211–218

    Article  PubMed  CAS  Google Scholar 

  39. Russo J, Romero AL, Russo IH (1994) Architectural pattern of the normal and cancerous breast under the influence of parity. Cancer Epidemiol Biomarkers Prev 3:219–224

    PubMed  CAS  Google Scholar 

  40. Russo J, Lynch H, Russo IH (2001) Mammary gland architecture as a determining factor in the susceptibility of the human breast to cancer. Breast J 7:278–291

    Article  PubMed  CAS  Google Scholar 

  41. Russo J, Balogh GA, Chen J, Fernandez SV, Fernbaugh R, Heulings R, Mailo DA, Moral R, Russo PA, Sheriff F, Vanegas JE, Wang R, Russo IH (2006) The concept of stem cell in the mammary gland and its implication in morphogenesis, cancer and prevention. Front Biosci 11:151–172

    Article  PubMed  CAS  Google Scholar 

  42. Smalley M, Ashworth A (2003) Stem cells and breast cancer: a field in transit. Nat Rev 3:832–844

    Article  CAS  Google Scholar 

  43. Stone J, Dite GS, Gunasekara A, English DR, McCredie MR, Giles GG, Cawson JN, Hegele RA, Chiarelli AM, Yaffe MJ, Boyd NF, Hopper JL (2006) The heritability of mammographically dense and nondense breast tissue. Cancer Epidemiol Biomarkers Prev 15:612–617

    Article  PubMed  Google Scholar 

  44. Stone J, Warren RM, Pinney E, Warwick J, Cuzick J (2009) Determinants of percentage and area measures of mammographic density. Am J Epidemiol 170:1571–1578

    Article  PubMed  Google Scholar 

  45. Tamimi RM, Cox D, Kraft P, Colditz GA, Hankinson SE, Hunter DJ (2008) Breast cancer susceptibility loci and mammographic density. Breast Cancer Res 10:R66

    Article  PubMed  Google Scholar 

  46. Turashvili G, McKinney S, Martin L, Gelmon KA, Watson P, Boyd N, Aparicio S (2009) Columnar cell lesions, mammographic density and breast cancer risk. Breast Cancer Res Treat 115:561–571

    Article  PubMed  Google Scholar 

  47. Vachon CM, Kuni CC, Anderson K, Anderson VE, Sellers TA (2000) Association of mammographically defined percent breast density with epidemiologic risk factors for breast cancer (United States). Cancer Causes Control 11:653–662

    Article  PubMed  CAS  Google Scholar 

  48. 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 

  49. Vogel WF, Aszodi A, Alves F, Pawson T (2001) Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development. Mol Cell Biol 21:2906–2917

    Article  PubMed  CAS  Google Scholar 

  50. Wolfe JN (1976) Breast patterns as an index of risk for developing breast cancer. AJR 126:1130–1137

    PubMed  CAS  Google Scholar 

  51. Woodward WA, Chen MS, Behbod F, Rosen JM (2005) On mammary stem cells. J Cell Sci 118:3585–3594

    Article  PubMed  CAS  Google Scholar 

  52. Yaffe M, Boyd N (2005) Mammographic breast density and cancer risk: the radiological view. Gynecol Endocrinol 21(Suppl 1):6–11

    Article  PubMed  Google Scholar 

  53. Zhu X, Asa SL, Ezzat S (2009) Histone-acetylated control of fibroblast growth factor receptor 2 intron 2 polymorphisms and isoform splicing in breast cancer. Mol Endocrinol 23:1397–1405

    Article  PubMed  CAS  Google Scholar 

  54. Zhu X, Asa SL, Ezzat S (2010) Genetic and epigenetic mechanisms down-regulate FGF receptor 2 to induce melanoma-associated antigen a in breast cancer. Am J Pathol 176:2333–2343

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Victorian Breast Cancer Research Consortium (MCS, IGC, EWT, JH), the St. Vincent’s Hospital Research Endowment Fund (EWT, JC, PH 2008, 2009), National Health and Medical Research Council (MCS, JH, IGC) and the Agency for Science Technology and Research (A*STAR) (NSS-PhD award to SJL). We thank Sue MacAuley, Zara Werts and Nadine Wood (St Vincent’s BreastScreen, St. Vincent’s Hospital, Victoria) for help with radiography and tissue sampling; Dyan Chitty (The University of Melbourne) and Annabel Southey (St. Vincent’s Institute) for help with histological counts; Tony Blick and Dexing Huang (St. Vincent’s Institute) for help with tissue accrual and Faxitron imaging; The Victorian Cancer Biobank and Samantha Boyle (Peter MacCallum Cancer Centre) for help with tissue accrual; Kevin Nguyen and Jacob Fry (The University of Melbourne) for help with X-ray film digitisation; Joshy George (Peter MacCallum Cancer Centre) for statistical consultation; Lilian Soon (University of Sydney) for early histological analysis; Tina Cardamone and Louise Pontell (The Australian Phenomics Network, The University of Melbourne) for help with slide scanning.

Competing interests

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Erik W. Thompson.

Additional information

Ian G. Campbell and Erik W. Thompson shared senior authorship.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 17 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, S.J., Cawson, J., Hill, P. et al. Image-guided sampling reveals increased stroma and lower glandular complexity in mammographically dense breast tissue. Breast Cancer Res Treat 128, 505–516 (2011). https://doi.org/10.1007/s10549-011-1346-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1346-0

Keywords

Navigation