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Gene expression profiling of luminal B breast cancers reveals NHERF1 as a new marker of endocrine resistance

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Abstract

The luminal B subtype represents a group of high proliferating estrogen receptor positive breast cancers which are associated with a poor prognosis. Genes exclusively expressed in this subtype should help to better understand these tumors. In a finding cohort of 171 breast cancers luminal B specific genes were identified displaying strong expression in highly proliferating Ki-67 positive/ER positive tumors but no expression either in Ki-67 negative/ER positive or in Ki-67 positive/ER negative samples. The clinical relevance of the scaffold protein NHERF1 identified by this strategy was assessed in a total of 3,030 breast cancers. NHERF1 expression was associated with the luminal B subtype both in the finding and validation cohort. A positive correlation of NHERF1 expression with tumor size (P < 0.001), grade (P < 0.001), and HER2 status (P = 0.033) was observed. NHERF1 expression was associated with a worse survival in ER positive breast cancer (P < 0.001) and retained its prognostic value in multivariate analysis. For ER positive samples with low NHERF1 expression a benefit of endocrine therapy was detected (P = 0.007). In contrast no differences in disease free survival were found for high NHERF1 expressing breast cancers which were either treated with endocrine therapy or no systemic therapy. Our data indicate that NHERF1 expressing breast cancers seem to have a greater risk to develop resistance to endocrine therapy. However, based on previous findings of NHERF1 functioning in PI3K signalling from basic research, these tumors might be appropriate candidates for a targeted therapy of the PI3K/Akt pathway.

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Abbreviations

ER:

Estrogen receptor

HER2:

Human epidermal growth factor receptor 2

NHERF1:

Na/H exchanger regulatory factor 1

PDGFR:

Platelet-derived growth factor receptor

PTEN:

Phosphatase and tensin homolog deleted on chromosome 10

PDZ:

PSD-95/DlgA/zo-1

MERM:

Merlin–ezrin–radixin–moesin

DDR1:

Discoidin Domain Receptor 1

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Acknowledgments

We thank Katherina Kourtis and Samira Adel for expert technical assistance. This study was supported by grants from the H.W. & J. Hector-Stiftung, Mannheim, the Margarete Bonifer-Stiftung, Bad Soden, the BANSS-Stiftung, Biedenkopf, and the Dr. Robert Pfleger-Stiftung, Bamberg.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, J. W. Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany

    Thomas Karn, Eugen Ruckhäberle, Lars Hanker, Christine Solbach, Regine Gätje, Uwe Holtrich, Manfred Kaufmann & Achim Rody

  2. Department of Obstetrics and Gynecology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Volkmar Müller

  3. Department of Obstetrics and Gynecology, Gutenberg-University, Mainz, Germany

    Marcus Schmidt

  4. Siemens Diagnostics, Leverkusen, Germany

    Mathias Gehrmann

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Karn, T., Ruckhäberle, E., Hanker, L. et al. Gene expression profiling of luminal B breast cancers reveals NHERF1 as a new marker of endocrine resistance. Breast Cancer Res Treat 130, 409–420 (2011). https://doi.org/10.1007/s10549-010-1333-x

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