Breast Cancer Research and Treatment

, Volume 129, Issue 1, pp 49–67 | Cite as

MPA-induced gene expression and stromal and parenchymal gene expression profiles in luminal murine mammary carcinomas with different hormonal requirements

  • Sebastián Giulianelli
  • Jason I. Herschkowitz
  • Vyomesh Patel
  • Caroline A. Lamb
  • J. Silvio Gutkind
  • Alfredo Molinolo
  • Charles M. Perou
  • Claudia Lanari
Preclinical study
First Online:
Received:
Accepted:

Abstract

Over the past several years, we have been interested in understanding the mechanisms by which mammary carcinomas acquire hormone independence. We demonstrated that carcinoma associated fibroblasts participate in the ligand-independent activation of progesterone receptors inducing tumor growth. In this study, we used DNA microarrays to compare the gene expression profiles of tumors from the MPA mouse breast cancer model, one hormone-dependent (C4-HD) and one hormone-independent (C4-HI), using whole tumor samples or laser-captured purified stromal and epithelial cells obtained from the same tumors. The expression of selected genes was validated by immunohistochemistry and immunofluorescence assays. We identified 413 genes specifically expressed in tumor stroma. Eighty-five percent of these genes were upregulated, whereas the remaining 15% were downregulated in C4-HI relative to their expression in the C4-HD tumor stroma. Several matrix metallopeptidases were overexpressed in the C4-HI tumor microenvironment. On the other hand, 1100 genes were specifically expressed in the tumor parenchyma. Among them, the 29% were upregulated, whereas the remaining 71% were downregulated in C4-HI relative to C4-HD tumor epithelium. Steap, Pdgfc, Runx2, Cxcl9, and Sdf2 were among the genes with high expression in the C4-HI tumor parenchyma. Interestingly, Fgf2 was one of the few genes upregulated by MPA in C4-HD tumors, confirming its pivotal role in regulating tumor growth in this model. In conclusion, we demonstrate herein a gene expression profile that distinguishes both the epithelial and the stromal cells in mammary tumors with different hormone dependence, supporting the hypothesis that the tumor-associated stroma may contribute to hormone-independent tumor growth.

Keywords

Breast cancer Epithelium Tumor stroma DNA microarray analysis 

Abbreviations

CAFs

Carcinoma-associated fibroblasts

DCIS

Ductal carcinoma in situ

EASE

Expression analysis systematic explorer

ER

Estrogen receptor

FDR

False discovery rate

GO

Gene ontology

H&E

Hematoxylin and eosin

HD

Hormone-dependent or MPA-dependent tumor

HI

Hormone-independent or MPA-independent tumor

IDC

Invasive ductal carcinomas

LCM

Laser capture microdissection

MPA

Medroxyprogesterone acetate

NAFs

Normal-associated fibroblasts

PI

Propidium iodide

PR

Progesterone receptor

SAM

Significance analysis of microarrays

s.c.

Subcutaneous

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Notes

Acknowledgments

We are very grateful to Julieta Bolado for excellent technical support and to Laboratorios Craveri (Buenos Aires, Argentina) for providing MPA. SG received an award from Avon Foundation for data presented at the AACR Annual Meeting 2008, and an ICRETT Fellowship from the UICC permitting training in Dr Perou’s laboratory. This work was supported by Fundación Sales, SECyT (PICT 2005 and 2007-932), and CONICET (PIP 5351) to CL.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Sebastián Giulianelli
    • 1
  • Jason I. Herschkowitz
    • 2
  • Vyomesh Patel
    • 3
  • Caroline A. Lamb
    • 1
  • J. Silvio Gutkind
    • 3
  • Alfredo Molinolo
    • 3
  • Charles M. Perou
    • 4
  • Claudia Lanari
    • 1
  1. 1.Laboratory of Hormonal CarcinogenesisInstituto de Biología y Medicina Experimental (Consejo Nacional de Investigaciones Científicas y Técnicas—CONICET)Buenos AiresArgentina
  2. 2.Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonUSA
  3. 3.Oral and Pharyngeal Cancer BranchNational Institute of Dental and Craniofacial Research, NIHBethesdaUSA
  4. 4.Departments of Genetics and of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer CenterUniversity of North CarolinaChapel HillUSA

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