J Breast Cancer.  2006 Sep;9(3):184-192. 10.4048/jbc.2006.9.3.184.

Expression of the Markers for the Mammary Stem Cells and the Cellular Lineages of the Mammary Gland on Ductal Carcinoma In Situ

• Jo BH
• Kim HJ
• Kim YJ
• Park Y
• Lee IK
• Kim DI
• Lee WH
• Yoon SO

• KMID: 2286648
• DOI: http://doi.org/10.4048/jbc.2006.9.3.184

Abstract

PURPOSE
Breast Cancer is an inter-tumoral and intra-tumoral heterogeneous disease. It remains unclear whether this heterogeneity results from different target cells or from different subsets of genetic abnormalities, otherwise from both. We postulated that in addition to genetic cloning, a variety of cells that exist during the defined developmental stages of the human mammary gland could give rise to the heterogeneity of breast cancer. To verify this postulation, we have analyzed pure ductal carcinoma in situ (DCIS) for the expression of the biomarkers that represent the mammary stem cell, the early progenitor cells, and the glandular and myoepithelial cells of the mammary gland.
METHODS
We investigated the relationship between the immnuohistochemical expression of the mammary development-associated biomarkers {cytokeratin-18 (CK18), cytokeratin-6 (CK6), alpha-smooth muscle actin (SMA), Wnt-1, Notch 3} and some other factors {the menopausal status, the estrogen receptor (ER) status, the progesterone receptor (PR) status, c-erbB-2, and the number of tumor foci} in 26 cases of DCIS.
RESULTS
All 26 cases included in this study showed the positive expressions of CK18 and SMA. The expression of all the markers was not correlated with the menopausal status. The positive expression of CK6 had a statistically significant relationship with a negative estrogen receptor (p=0.014), positive c-erbB-2 (p=0.048), high nuclear grade (p=0.001), and single focus of DCIS (p=0.017). The expression of Wnt-1 and Notch 3 did not have significant correlation with any factors. However, the positive expression of Wnt-1 showed a tendency of a negative ER (p=0.061) and the positive expression of Notch 3 also showed a tendency of a negative ER (p=0.086) and a high nuclear grade (p=0.086).
CONCLUSION
The CK6 positive tumor is thought to originate from the more primitive cells compared to the CK6 negative tumor. Unifocality of the CK positive tumor might result from the arrest of differentiation of the original cell after disease affection. DCISs could be categorized into the CK6 positive and negative groups.

Keyword

Heterogeneity; Target cells; ductal carcinoma in situ; Arrest of Differentiation

MeSH Terms

Actins
Biomarkers
Breast Neoplasms
Carcinoma, Ductal*
Carcinoma, Intraductal, Noninfiltrating*
Clone Cells
Cloning, Organism
Estrogens
Keratin-6
Mammary Glands, Human*
Population Characteristics
Receptors, Progesterone
Stem Cells*
Actins
Estrogens
Keratin-6
Receptors, Progesterone

Reference

1. The Korean Breast Cancer Society. Nationwide Korean breast cancer data of 2002. J Korean Breast Cancer Soc. 2004. 7:72–83.

2. Anderson WF, Chu KC, Devesa SS. Distinct incidence patterns among in situ and invasive breast carcinomas, with possible etiologic implications. Breast Cancer Res Treat. 2004. 88:149–159.

3. O'Connell P, Pekkel V, Fuqua SA, Osborne CK, Clark GM, Allred DC. Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. J Natl Cancer Inst. 1998. 90:697–703.

4. Li Y, Rosen JM. Stem/progenitor cells in mouse mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia. 2005. 10:17–24.

5. Hennighausen L, Robinson GW. Signaling pathways in mammary gland development. Dev Cell. 2001. 1:467–475.

6. Duncan AW, Rattis FM, DiMascio LN, Congdon KL, Pazianos G, Zhao C, et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat Immunol. 2005. 6:314–322.

7. Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 2003. 17:1253–1270.

8. Abd El-Rehim DM, Pinder SE, Paish CE, Bell J, Blamey RW, Robertson JF, et al. Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol. 2004. 203:661–671.

9. Woelfle U, Sauter G, Santjer S, Brakenhoff R, Pantel K. Down-regulated expression of cytokeratin 18 promotes progression of human breast cancer. Clin Cancer Res. 2004. 10:2670–2674.

10. Potemski P, Kusinska R, Watala C, Pluciennik E, Bednarek AK, Kordek R. Prognostic relevance of basal cytokeratin expression in operable breast cancer. Oncology. 2005. 69:478–485.

11. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004. 10:5367–5374.

12. Silverstein MJ, Poller DN, Waisman JR, Colburn WJ, Barth A, Gierson ED, et al. Prognostic classification of breast ductal carcinoma-in-situ. Lancet. 1995. 345:1154–1157.

13. Buerger H, Otterbach F, Simon R, Poremba C, Diallo R, Decker T, et al. Comparative genomic hybridization of ductal carcinoma in situ of the breast-evidence of multiple genetic pathways. J Pathol. 1999. 187:396–402.

14. DeOme KB, Faulkin LJ Jr, Bern HA, Blair PB. Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Res. 1959. 19:515–520.

15. Daniel CW, Young LJ, Medina D, DeOme KB. The influence of mammogenic hormones on serially transplanted mouse mammary gland. Exp Gerontol. 1971. 6:95–101.

16. Kordon EC, Smith GH. An entire functional mammary gland may comprise the progeny from a single cell. Development. 1998. 125:1921–1930.

17. Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS. Stem cells in normal breast development and breast cancer. Cell Prolif. 2003. 36:59–72.

18. Brennan KR, Brown AM. Wnt proteins in mammary development and cancer. J Mammary Gland Biol Neoplasia. 2004. 9:119–131.

19. Rijsewijk F, Schuermann M, Wagenaar E, Parren P, Weigel D, Nusse R. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell. 1987. 50:649–657.

20. Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, et al. Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci U S A. 2000. 97:4262–4266.

21. Man YG, Tai L, Barner R, Vang R, Saenger JS, Shekitka KM, et al. Cell clusters overlying focally disrupted mammary myoepithelial cell layers and adjacent cells within the same duct display different immunohistochemical and genetic features: implications for tumor progression and invasion. Breast Cancer Res. 2003. 5:R231–R241.

22. Soriano JV, Uyttendaele H, Kitajewski J, Montesano R. Expression of an activated Notch4(int-3) oncoprotein disrupts morphogenesis and induces an invasive phenotype in mammary epithelial cells in vitro. Int J Cancer. 2000. 86:652–659.

23. Bocker W, Moll R, Poremba C, Holland R, Van Diest PJ, Dervan P, et al. Common adult stem cells in the human breast give rise to glandular and myoepithelial cell lineages: a new cell biological concept. Lab Invest. 2002. 82:737–746.

24. Takahashi K, Paladini RD, Coulombe PA. Cloning and characterization of multiple human genes and cDNAs encoding highly related type II keratin 6 isoforms. J Biol Chem. 1995. 270:18581–18592.

25. Taylor-Papadimitriou J, Lane EB. Daniel CW, editor. Keratin expression in the mammary gland. The Mammary Gland: Development Regulation and Function. 1987. Newyork: Plenum;181–215.