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

  • Preclinical study
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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.

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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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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.

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Authors and Affiliations

  1. Laboratory of Hormonal Carcinogenesis, Instituto de Biología y Medicina Experimental (Consejo Nacional de Investigaciones Científicas y Técnicas—CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina

    Sebastián Giulianelli, Caroline A. Lamb & Claudia Lanari

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Jason I. Herschkowitz

  3. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA

    Vyomesh Patel, J. Silvio Gutkind & Alfredo Molinolo

  4. Departments of Genetics and of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    Charles M. Perou

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  1. Sebastián Giulianelli
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  2. Jason I. Herschkowitz
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  3. Vyomesh Patel
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  4. Caroline A. Lamb
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  5. J. Silvio Gutkind
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  6. Alfredo Molinolo
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  7. Charles M. Perou
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  8. Claudia Lanari
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Correspondence to Claudia Lanari.

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Giulianelli, S., Herschkowitz, J.I., Patel, V. et al. MPA-induced gene expression and stromal and parenchymal gene expression profiles in luminal murine mammary carcinomas with different hormonal requirements. Breast Cancer Res Treat 129, 49–67 (2011). https://doi.org/10.1007/s10549-010-1185-4

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