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HIF-1α and NOTCH signaling in ductal and lobular carcinomas of the breast

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Abstract

Background

NOTCH signaling is involved in every step of metazoan development and maintenance of adult tissue homeostasis. It is frequently deregulated by mutations and overexpression in different cancer types including solid tumors such as breast cancer. Another common feature of solid tumors is hypoxia, which occurs due to defective or insufficient vascularization. Hypoxia-inducible factors (HIFs) are key regulators of the homeostatic response to low oxygen levels. HIF-1α is overexpressed in many solid tumors, including breast cancer. Hypoxia-induced stabilization of HIF transcription factors has been shown to lead to NOTCH activation in vitro in different contexts and tissues, causing differentiation arrest and induction of proliferation and migration.

Methods

Since the link between HIF-1α and NOTCH signalling has hardly been studied, we set out to closely investigate associations between the expression of HIF-1α and NOTCH pathway members in primary and metastatic human breast cancer specimens and their prognostic value.

Results

Co-expression of NOTCH1 intracellular domain (N1ICD) and HIF-1α was associated with a high grade and a high proliferation rate in invasive breast cancer. HIF-1α expression was low in classic, but high in pleomorphic lobular cancers, which also frequently showed stromal HIF-1α expression. NOTCH1 pathway activation was prognostically unfavorable.

Conclusion

In breast cancer, NOTCH pathway activation appears to be associated with a poor prognosis, but NOTCH and HIF signaling do not seem to be functionally associated.

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Acknowledgements

The authors acknowledge Iordanka Ivanova for helpful suggestions and critical input.

Conflict of interest

The authors declare no conflict of interests.

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Authors and Affiliations

  1. Department of Pathology, University Medical Center Utrecht Cancer Center, PO Box 85500, 3508 GA, Utrecht, The Netherlands

    Cigdem Ercan, Jeroen F. Vermeulen, Laurien Hoefnagel, Petra van der Groep & Paul J. van Diest

  2. Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Peter Bult

  3. Division of Internal Medicine and Dermatology, University Medical Center Utrecht, Oost, The Netherlands

    Elsken van der Wall

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  1. Cigdem Ercan
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  2. Jeroen F. Vermeulen
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Correspondence to Paul J. van Diest.

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Ercan, C., Vermeulen, J.F., Hoefnagel, L. et al. HIF-1α and NOTCH signaling in ductal and lobular carcinomas of the breast. Cell Oncol. 35, 435–442 (2012). https://doi.org/10.1007/s13402-012-0102-8

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