Top

Published in:

Open Access 01-06-2013 | Research article

Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15

Authors: Jacqueline Lehmann-Che, Anne-Sophie Hamy, Raphaël Porcher, Marc Barritault, Fatiha Bouhidel, Hanadi Habuellelah, Solenne Leman-Detours, Anne de Roquancourt, Laurence Cahen-Doidy, Edwige Bourstyn, Patricia de Cremoux, Cedric de Bazelaire, Marcela Albiter, Sylvie Giacchetti, Caroline Cuvier, Anne Janin, Marc Espié, Hugues de Thé, Philippe Bertheau

Published in: Breast Cancer Research | Issue 3/2013

Abstract

Introduction

Molecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors.

Methods

We performed quantitative reverse transcription PCR (qRT-PCR) for ESR1, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, Human Epidermal Growth Factor Receptor 2 (HER2), CK5/6, CK17, EGFR, Ki67, AR, FOXA1 and GCDFP15 and we analyzed clinical features.

Results

MA tumors were all characterized by ESR1(-) AR(+) FOXA1(+) and AR-related genes positive mRNA profile. IHC staining on these tumors showed 93% ER(-), only 58% AR(+) and 90% FOXA1(+). 67% and 57% MA tumors were HER2(3+) and GCDFP15(+), respectively. Almost all MA tumors (94%) had the IHC signature HER2(3+) or GCDFP15(+) but none of the 13 control basal-like (BL) tumors did. Clinically, MA tumors were rather aggressive, with poor prognostic factors.

Conclusion

MA tumors could be better defined by their qRT-PCR-AR profile than by AR IHC. In addition, we found that HER2 or GCDFP15 protein overexpression is a sensitive and specific tool to differentiate MA from BL in the context of ER negative tumors. A composite molecular and IHC signature could, therefore, help to identify MA tumors in daily practice.

Available only for authorised users

Birrell SN, Hall RE, Tilley WD: Role of the androgen receptor in human breast cancer. J Mammary Gland Biol Neoplasia. 1998, 3: 95-103. 10.1023/A:1018730519839.CrossRefPubMed

Park S, Koo J, Park HS, Kim J-H, Choi S-Y, Lee JH, Park B-W, Lee KS: Expression of androgen receptors in primary breast cancer. Ann Oncol. 2010, 21: 488-492. 10.1093/annonc/mdp510.CrossRefPubMed

Farmer P, Bonnefoi H, Becette V, Tubiana-Hulin M, Fumoleau P, Larsimont D, Macgrogan G, Bergh J, Cameron D, Goldstein D, Duss S, Nicoulaz A-L, Brisken C, Fiche M, Delorenzi M, Iggo R: Identification of molecular apocrine breast tumours by microarray analysis. Oncogene. 2005, 24: 4660-4671. 10.1038/sj.onc.1208561.CrossRefPubMed

Doane AS, Danso M, Lal P, Donaton M, Zhang L, Hudis C, Gerald WL: An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene. 2006, 25: 3994-4008. 10.1038/sj.onc.1209415.CrossRefPubMed

Guedj M, Marisa L, de Reynies A, Orsetti B, Schiappa R, Bibeau F, MacGrogan G, Lerebours F, Finetti P, Longy M, Bertheau P, Bertrand F, Bonnet F, Martin AL, Feugeas JP, Bièche I, Lehmann-Che J, Lidereau R, Birnbaum D, Bertucci F, de Thé H, Theillet C: A refined molecular taxonomy of breast cancer. Oncogene. 2012, 31: 1196-1206. 10.1038/onc.2011.301.CrossRefPubMed

Moinfar F, Okcu M, Tsybrovskyy O, Regitnig P, Lax SF, Weybora W, Ratschek M, Tavassoli FA, Denk H: Androgen receptors frequently are expressed in breast carcinomas: potential relevance to new therapeutic strategies. Cancer. 2003, 98: 703-711. 10.1002/cncr.11532.CrossRefPubMed

Marisa L, de Reynies A, Guedj M: citbcmst: Assigning tumor samples to CIT Breast Cancer Molecular Subtypes from gene expression data. [http://cran.r-project.org/web/packages/citbcmst/index.html]

Latil A, Bièche I, Vidaud D, Lidereau R, Berthon P, Cussenot O, Vidaud M: Evaluation of androgen, estrogen (ERα and ERβ), and progesterone receptor expression in human prostate cancer by real-time quantitative reverse transcription-polymerase chain reaction assays. Cancer Res. 2001, 61: 1919-1926.PubMed

Budczies J, Klauschen F, Sinn BV, Győrffy B, Schmitt WD, Darb-Esfahani S, Denkert C: Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE. 2012, 7: e51862-10.1371/journal.pone.0051862.CrossRefPubMedPubMedCentral

10.

Lehmann-Che J, Amira-Bouhidel F, Turpin E, Antoine M, Soliman H, Legres L, Bocquet C, Bernoud R, Flandre E, Varna M, de Roquancourt A, Plassa L-F, Giacchetti S, Espié M, de Bazelaire C, Cahen-Doidy L, Bourstyn E, Janin A, de Thé H, Bertheau P: Immunohistochemical and molecular analyses of HER2 status in breast cancers are highly concordant and complementary approaches. Br J Cancer. 2011, 104: 1739-1746. 10.1038/bjc.2011.135.CrossRefPubMedPubMedCentral

11.

Flaman JM, Frebourg T, Moreau V, Charbonnier F, Martin C, Chappuis P, Sappino AP, Limacher IM, Bron L, Benhattar J: A simple p53 functional assay for screening cell lines, blood, and tumors. Proc Natl Acad Sci USA. 1995, 92: 3963-3967. 10.1073/pnas.92.9.3963.CrossRefPubMedPubMedCentral

12.

Waridel F, Estreicher A, Bron L, Flaman JM, Fontolliet C, Monnier P, Frebourg T, Iggo R: Field cancerisation and polyclonal p53 mutation in the upper aero-digestive tract. Oncogene. 1997, 14: 163-169. 10.1038/sj.onc.1200812.CrossRefPubMed

13.

Varna M, Lehmann-Che J, Turpin E, Marangoni E, El Bouchtaoui M, Jeanne M, Grigoriu C, Ratajczak P, Leboeuf C, Plassa L-F, Ferreira I, Poupon M-F, Janin A, de Thé H, Bertheau P: p53 dependent cell cycle arrest triggered by chemotherapy in xenografted breast tumors. Int J Cancer. 2009, 124: 991-997. 10.1002/ijc.24049.CrossRefPubMed

14.

Santarpia M, Altavilla G, Margeli M, Cirauqui B, Mesiti M, Cavallari V, Ramirez JL, Sanchez-Ronco M, Santarpia L, Taron M, Rosell R: PIK3CA mutations and BRCA1 expression in breast cancer: potential biomarkers for chemoresistance. Cancer Invest. 2008, 26: 1044-1051. 10.1080/07357900802112701.CrossRefPubMed

15.

Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF, American Society of Clinical Oncology/College of American Pathologists: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007, 131: 18-43.PubMed

16.

Gown AM: Current issues in ER and HER2 testing by IHC in breast cancer. Mod Pathol. 2008, 21 (Suppl 2): S8-S15.CrossRefPubMed

17.

Breiman L, Friedman JH, Olshen RA, Stone CJ: Classification and Regression Trees. 1984, London: Chapman and Hall

18.

Shih Y-S: Selecting the best splits for classification trees with categorical variables. Stat Probabil Lett. 2001, 54: 341-345. 10.1016/S0167-7152(00)00188-7.CrossRef

19.

R Development Core Team: R: A Language and Environment for Statistical Computing. 2009, Vienna, Austria: R Foundation for Statistical Computing

20.

Ripley B: Tree: Classifcation and Regression Trees. 2010, [http://CRAN.R-project.org/package=tree] . R package version 1.0-28

21.

O'Malley FP, Page DL, Nelson EH, Dupont WD: Ductal carcinoma in situ of the breast with apocrine cytology: definition of a borderline category. Hum Pathol. 1994, 25: 164-168. 10.1016/0046-8177(94)90273-9.CrossRefPubMed

22.

Tavassoli FA, Norris HJ: Intraductal apocrine carcinoma: a clinicopathologic study of 37 cases. Mod Pathol. 1994, 7: 813-818.PubMed

23.

Tavassoli FA, Devilee P, World Health Organization: Tumours of the Breast and Female Genital Organs - Pathology and Genetics. 2003, Lyon, France: IARC Press

24.

Zagorianakou P, Zagorianakou N, Stefanou D, Makrydimas G, Agnantis NJ: The enigmatic nature of apocrine breast lesions. Virchows Arch. 2006, 448: 525-531. 10.1007/s00428-005-0095-z.CrossRefPubMed

25.

Weigelt B, Horlings HM, Kreike B, Hayes MM, Hauptmann M, Wessels LF, de Jong D, Van de Vijver MJ, Van't Veer LJ, Peterse JL: Refinement of breast cancer classification by molecular characterization of histological special types. J Pathol. 2008, 216: 141-150. 10.1002/path.2407.CrossRefPubMed

26.

Celis JE, Cabezón T, Moreira JM, Gromov P, Gromova I, Timmermans-Wielenga V, Iwase T, Akiyama F, Honma N, Rank F: Molecular characterization of apocrine carcinoma of the breast: validation of an apocrine protein signature in a well-defined cohort. Mol Oncol. 2009, 3: 220-237. 10.1016/j.molonc.2009.01.005.CrossRefPubMed

27.

Vranic S, Gatalica Z, Deng H, Frkovic-Grazio S, Lee LM, Gurjeva O, Wang ZY: ER-α36, a novel isoform of ER-α66, is commonly over-expressed in apocrine and adenoid cystic carcinomas of the breast. J Clin Pathol. 2011, 64: 54-57. 10.1136/jcp.2010.082776.CrossRefPubMed

28.

Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM, Bhargava R: Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol. 2010, 23: 205-212. 10.1038/modpathol.2009.159.CrossRefPubMed

29.

Albergaria A, Paredes J, Sousa B, Milanezi F, Carneiro V, Bastos J, Costa S, Vieira D, Lopes N, Lam EW, Lunet N, Schmitt F: Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours. Breast Cancer Res. 2009, 11: R40-10.1186/bcr2327.CrossRefPubMedPubMedCentral

30.

Baniwal SK, Little GH, Chimge N-O, Frenkel B: Runx2 controls a feed-forward loop between androgen and prolactin-induced protein (PIP) in stimulating T47D cell proliferation. J Cell Physiol. 2012, 227: 2276-2282. 10.1002/jcp.22966.CrossRefPubMedPubMedCentral

31.

Wick MR, Lillemoe TJ, Copland GT, Swanson PE, Manivel JC, Kiang DT: Gross cystic disease fluid protein-15 as a marker for breast cancer: immunohistochemical analysis of 690 human neoplasms and comparison with alpha-lactalbumin. Hum Pathol. 1989, 20: 281-287. 10.1016/0046-8177(89)90137-8.CrossRefPubMed

32.

Gonzalez-Angulo AM, Stemke-Hale K, Palla SL, Carey M, Agarwal R, Meric-Berstam F, Traina TA, Hudis C, Hortobagyi GN, Gerald WL, Mills GB, Hennessy BT: Androgen receptor levels and association with PIK3CA mutations and prognosis in breast cancer. Clin Cancer Res. 2009, 15: 2472-2478. 10.1158/1078-0432.CCR-08-1763.CrossRefPubMed

33.

Alimirah F, Panchanathan R, Chen J, Zhang X, Ho SM, Choubey D: Expression of androgen receptor is negatively regulated by p53. Neoplasia. 2007, 9: 1152-1159. 10.1593/neo.07769.CrossRefPubMedPubMedCentral

34.

Collins LC, Cole KS, Marotti JD, Hu R, Schnitt SJ, Tamimi RM: Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses' Health Study. Mod Pathol. 2011, 24: 924-931. 10.1038/modpathol.2011.54.CrossRefPubMedPubMedCentral

35.

Loibl S, Müller BM, von Minckwitz G, Schwabe M, Roller M, Darb-Esfahani S, Ataseven B, du Bois A, Fissler-Eckhoff A, Gerber B, Kulmer U, Alles JU, Mehta K, Denkert C: Androgen receptor expression in primary breast cancer and its predictive and prognostic value in patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat. 2011, 130: 477-487. 10.1007/s10549-011-1715-8.CrossRefPubMed

36.

Gonzalez LO, Corte MD, Vazquez J, Junquera S, Sanchez R, Alvarez AC, Rodriguez JC, Lamelas ML, Vizoso FJ: Androgen receptor expression in breast cancer: relationship with clinicopathological characteristics of the tumors, prognosis, and expression of metalloproteases and their inhibitors. BMC Cancer. 2008, 8: 149-10.1186/1471-2407-8-149.CrossRefPubMedPubMedCentral

37.

Hu R, Dawood S, Holmes MD, Collins LC, Schnitt SJ, Cole K, Marotti JD, Hankinson SE, Colditz GA, Tamimi RM: Androgen receptor expression and breast cancer survival in postmenopausal women. Clin Cancer Res. 2011, 17: 1867-1874. 10.1158/1078-0432.CCR-10-2021.CrossRefPubMedPubMedCentral

38.

Agoff SN, Swanson PE, Linden H, Hawes SE, Lawton TJ: Androgen receptor expression in estrogen receptor-negative breast cancer. Immunohistochemical, clinical, and prognostic associations. Am J Clin Pathol. 2003, 120: 725-731. 10.1309/42F00D0DJD0J5EDT.CrossRefPubMed

39.

Luo X, Shi Y-X, Li Z-M, Jiang W-Q: Expression and clinical significance of androgen receptor in triple negative breast cancer. Chin J Cancer. 2010, 29: 585-590. 10.5732/cjc.009.10673.CrossRefPubMed

40.

Banneau G, Guedj M, MacGrogan G, de Mascarel I, Velasco V, Schiappa R, Bonadona V, David A, Dugast C, Gilbert-Dussardier B, Ingster O, Vabres P, Caux F, de Reynies A, Iggo R, Sevenet N, Bonnet F, Longy M: Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations. Breast Cancer Res. 2010, 12: R63-10.1186/bcr2626.CrossRefPubMedPubMedCentral

41.

Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011, 121: 2750-2767. 10.1172/JCI45014.CrossRefPubMedPubMedCentral

Title: Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15
Authors: Jacqueline Lehmann-Che
Anne-Sophie Hamy
Raphaël Porcher
Marc Barritault
Fatiha Bouhidel
Hanadi Habuellelah
Solenne Leman-Detours
Anne de Roquancourt
Laurence Cahen-Doidy
Edwige Bourstyn
Patricia de Cremoux
Cedric de Bazelaire
Marcela Albiter
Sylvie Giacchetti
Caroline Cuvier
Anne Janin
Marc Espié
Hugues de Thé
Philippe Bertheau
Publication date: 01-06-2013
Publisher: BioMed Central
Published in: Breast Cancer Research / Issue 3/2013
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/bcr3421

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 3/2013

DNA methylation in ductal carcinoma in situof the breast

COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration

Delivery of gene silencing agents for breast cancer therapy

Illuminating luminal B: QSOX1 as a subtype-specific biomarker

Disparities in breast cancer outcomes between Caucasian and African American women: a model for describing the relationship of biological and nonbiological factors

A randomized phase II presurgical trial of weekly low-dose tamoxifen versus raloxifene versus placebo in premenopausal women with estrogen receptor-positive breast cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer