Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Identification of molecular apocrine breast tumours by microarray analysis

Abstract

Previous microarray studies on breast cancer identified multiple tumour classes, of which the most prominent, named luminal and basal, differ in expression of the oestrogen receptor α gene (ER). We report here the identification of a group of breast tumours with increased androgen signalling and a ‘molecular apocrine’ gene expression profile. Tumour samples from 49 patients with large operable or locally advanced breast cancers were tested on Affymetrix U133A gene expression microarrays. Principal components analysis and hierarchical clustering split the tumours into three groups: basal, luminal and a group we call molecular apocrine. All of the molecular apocrine tumours have strong apocrine features on histological examination (P=0.0002). The molecular apocrine group is androgen receptor (AR) positive and contains all of the ER-negative tumours outside the basal group. Kolmogorov–Smirnov testing indicates that oestrogen signalling is most active in the luminal group, and androgen signalling is most active in the molecular apocrine group. ERBB2 amplification is commoner in the molecular apocrine than the other groups. Genes that best split the three groups were identified by Wilcoxon test. Correlation of the average expression profile of these genes in our data with the expression profile of individual tumours in four published breast cancer studies suggest that molecular apocrine tumours represent 8–14% of tumours in these studies. Our data show that it is possible with microarray data to divide mammary tumour cells into three groups based on steroid receptor activity: luminal (ER+ AR+), basal (ER− AR−) and molecular apocrine (ER− AR+).

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Bertucci F, Borie N, Ginestier C, Groulet A, Charafe-Jauffret E, Adelaide J, Geneix J, Bachelart L, Finetti P, Koki A, Hermitte F, Hassoun J, Debono S, Viens P, Fert V, Jacquemier J and Birnbaum D . (2004). Oncogene, 23, 2564–2575.

  • Birrell SN, Bentel JM, Hickey TE, Ricciardelli C, Weger MA, Horsfall DJ and Tilley WD . (1995). J. Steroid Biochem. Mol. Biol., 52, 459–467.

  • Birrell SN, Hall RE and Tilley WD . (1998). J. Mammary Gland Biol. Neoplasia, 3, 95–103.

  • Chamberlain NL, Driver ED and Miesfeld RL . (1994). Nucleic Acids Res., 22, 3181–3186.

  • Chen WY, Ramamoorthy P, Chen N, Sticca R and Wagner TE . (1999). Clin. Cancer Res., 5, 3583–3593.

  • Cormier-Regard S, Nguyen SV and Claycomb WC . (1998). J. Biol. Chem., 273, 17787–17792.

  • Denoyelle C, Albanese P, Uzan G, Hong L, Vannier JP, Soria J and Soria C . (2003). Cell Signal., 15, 327–338.

  • Ellis I . (2003). Pathology and Genetics of Tumours of the Breast and Female Genital Organs, Vol. 5: World Health Organization classification of tumours Tavassoli F, Devilee P (eds) IARC Press: Lyon, pp 13–59.

    Google Scholar 

  • Frable WJ and Kay S . (1968). Cancer, 21, 756–763.

  • Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR and Katzenellenbogen BS . (2003). Endocrinology, 144, 4562–4574.

  • Fuh G, Cunningham BC, Fukunaga R, Nagata S, Goeddel DV and Wells JA . (1992). Science, 256, 1677–1680.

  • Gess B, Hofbauer KH, Wenger RH, Lohaus C, Meyer HE and Kurtz A . (2003). Eur. J. Biochem., 270, 2228–2235.

  • Huang E, Cheng SH, Dressman H, Pittman J, Tsou MH, Horng CF, Bild A, Iversen ES, Liao M, Chen CM, West M, Nevins JR and Huang AT . (2003). Lancet, 361, 1590–1596.

  • Isola JJ, Kallioniemi OP, Chu LW, Fuqua SA, Hilsenbeck SG, Osborne CK and Waldman FM . (1995). Am. J. Pathol., 147, 905–911.

  • Jain AN, Chin K, Borresen-Dale AL, Erikstein BK, Eynstein Lonning P, Kaaresen R and Gray JW . (2001). Proc. Natl. Acad. Sci. USA, 98, 7952–7957.

  • Jones C, Damiani S, Wells D, Chaggar R, Lakhani SR and Eusebi V . (2001). Am. J. Pathol., 158, 207–214.

  • Labrie F, Luu-The V, Labrie C, Belanger A, Simard J, Lin SX and Pelletier G . (2003). Endocr. Rev., 24, 152–182.

  • Lamb J, Ramaswamy S, Ford HL, Contreras B, Martinez RV, Kittrell FS, Zahnow CA, Patterson N, Golub TR and Ewen ME . (2003). Cell, 114, 323–334.

  • La Spada AR, Wilson EM, Lubahn DB, Harding AE and Fischbeck KH . (1991). Nature, 352, 77–79.

  • Levesque E, Turgeon D, Carrier JS, Montminy V, Beaulieu M and Belanger A . (2001). Biochemistry, 40, 3869–3881.

  • Liao DJ and Dickson RB . (2002). J. Steroid. Biochem. Mol. Biol., 80, 175–189.

  • Lopez-Otin C and Diamandis EP . (1998). Endocr. Rev., 19, 365–396.

  • Mellinghoff IK, Vivanco I, Kwon A, Tran C, Wongvipat J and Sawyers CL . (2004). Cancer Cell, 6, 517–527.

  • Miller WR, Telford J, Dixon JM and Shivas AA . (1985). Breast Cancer Res. Treat., 5, 67–73.

  • Millward MJ, Cantwell BM, Dowsett M, Carmichael J and Harris AL . (1991). Br. J. Cancer, 63, 763–764.

  • Moinfar F, Okcu M, Tsybrovskyy O, Regitnig P, Lax SF, Weybora W, Ratschek M, Tavassoli FA and Denk H . (2003). Cancer, 98, 703–711.

  • Molist R, Remvikos Y, Dutrillaux B and Muleris M . (2004). Oncogene, 23, 5986–5993.

  • Nelson PS, Clegg N, Arnold H, Ferguson C, Bonham M, White J, Hood L and Lin B . (2002). Proc. Natl. Acad. Sci. USA, 99, 11890–11895.

  • Oettgen P, Finger E, Sun Z, Akbarali Y, Thamrongsak U, Boltax J, Grall F, Dube A, Weiss A, Brown L, Quinn G, Kas K, Endress G, Kunsch C and Libermann TA . (2000). J. Biol. Chem., 275, 1216–1225.

  • Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE and Meyerson M . (2004). Science, 304, 1497–1500.

  • Park H, Adams MA, Lachat P, Bosman F, Pang SC and Graham CH . (2000). Biochem. Biophys. Res. Commun., 276, 321–328.

  • Perou CM, Jeffrey SS, van de Rijn M, Rees CA, Eisen MB, Ross DT, Pergamenschikov A, Williams CF, Zhu SX, Lee JC, Lashkari D, Shalon D, Brown PO and Botstein D . (1999). Proc. Natl. Acad. Sci. USA, 96, 9212–9217.

  • Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO and Botstein D . (2000). Nature, 406, 747–752.

  • Pollack JR, Sorlie T, Perou CM, Rees CA, Jeffrey SS, Lonning PE, Tibshirani R, Botstein D, Borresen-Dale AL and Brown PO . (2002). Proc. Natl. Acad. Sci. USA, 99, 12963–12968.

  • Rosen PP . (1996). Diseases of the Breast Harris JR (ed) Lippincott: Philadelphia, pp 413–414.

    Google Scholar 

  • Rousseeuw PJ . (1987). J. Comput. Appl. Math., 20, 53–65.

  • Santen RJ, Manni A, Harvey H and Redmond C . (1990). Endocr. Rev., 11, 221–265.

  • Schmitt FC and Reis-Filho JS . (2002). Breast, 11, 463–465.

  • Selim AG, El-Ayat G and Wells CA . (2000). J. Pathol., 191, 138–142.

  • Selim AG and Wells CA . (1999). J. Clin. Pathol., 52, 838–841.

  • Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P and Borresen-Dale AL . (2001). Proc. Natl. Acad. Sci. USA, 98, 10869–10874.

  • Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL and Botstein D . (2003). Proc. Natl. Acad. Sci. USA, 100, 8418–8423.

  • Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL and Liu ET . (2003). Proc. Natl. Acad. Sci. USA, 100, 10393–10398.

  • van't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R and Friend SH . (2002). Nature, 415, 530–536.

  • Viacava P, Naccarato AG and Bevilacqua G . (1997). Virchows Arch., 431, 205–209.

  • Wennbo H and Tornell J . (2000). Oncogene, 19, 1072–1076.

  • West M, Blanchette C, Dressman H, Huang E, Ishida S, Spang R, Zuzan H, Olson Jr JA, Marks JR and Nevins JR . (2001). Proc. Natl. Acad. Sci. USA, 98, 11462–11467.

  • Wu L, Einstein M, Geissler WM, Chan HK, Elliston KO and Andersson S . (1993). J. Biol. Chem., 268, 12964–12969.

  • Yu H, Bharaj B, Vassilikos EJ, Giai M and Diamandis EP . (2000). Breast Cancer Res. Treat., 59, 153–161.

Download references

Acknowledgements

We thank the women participating in the EORTC 10994/BIG 00-01 study for generously donating tumour samples. We thank the doctors, nurses and data managers from the European Organization for Research and Treatment of Cancer (EORTC), the Anglo-Celtic Cooperative Oncology Group (ACCOG), the Swiss Group for Clinical Cancer Research (SAKK) and the Swedish Breast Cancer Group (SweBCG) for their active participation. We thank Annick Ducraux for technical assistance and Monica de Vos for data management. We thank Dr Wassim Raffoul for providing reduction mammoplasty tissue. We thank Dr Patrick Descombes for advice on chip hybridization and the Geneva NCCR ‘Frontiers in Genomics’ for use of their Affymetrix workstation. We thank Dr Michael Morris for measuring AR repeat length. We thank Drs Pascale Anderle, Thierry Sengstag and Viviane Praz for advice on Io and Cleanex. We thank Dr Felix Naef for helpful discussions on data analysis. We thank the Swiss National Science Foundation NCCR Molecular Oncology program, MEDIC Foundation, EORTC Translational Research Fund and Oncosuisse for financial support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard Iggo.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Farmer, P., Bonnefoi, H., Becette, V. et al. Identification of molecular apocrine breast tumours by microarray analysis. Oncogene 24, 4660–4671 (2005). https://doi.org/10.1038/sj.onc.1208561

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208561

Keywords

This article is cited by

Search

Quick links