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Comprehensive immunohistochemical analyses on expression levels of hedgehog signaling molecules in breast cancers

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Abstract

Background

The hedgehog (Hh) signaling pathway plays important roles in cell proliferation, malignant progression, invasion and metastasis, and the expansion of cancer stem cells (CSCs). Comprehensive immunohistochemical (IHC) analyses have not yet been conducted on the expression levels of Hh signaling molecules in breast cancer tissues.

Methods

A total of 204 patients with invasive breast cancer treated in our institute were study subjects. IHC analyses on the expression levels of the Hh signaling molecules, sonic Hh (SHH), PTCH1, GLI1, GLI2, and GLI3 and the CSC-related factor, SOX2, were investigated.

Results

Positive correlations were observed among all of the Hh signaling molecules tested. SOX2 expression correlated with the expression levels of all Hh signaling molecules. SHH expression positively correlated with tumor size, the Ki-67 labeling index, histological grade, estrogen receptor negativity, progesterone receptor negativity, and HER2 positivity. GLI1 expression positively correlated with the histological grade. GLI2 expression positively correlated with the histological grade, Ki-67 labeling index, and HER2 positivity. Univariate analyses revealed that a younger age, larger tumor size, positive lymph node metastasis, higher histological grade, positive lymphatic invasion, and higher Ki-67 labeling index were related to poor relapse-free survival (RFS). The positivity of all Hh signaling molecules and SOX2 did not correlate with poor RFS. A multivariate analysis revealed that positive lymphatic invasion and a younger age were independent worse prognostic factors for RFS.

Conclusions

This comprehensive analysis demonstrated for the first time that SHH, GLI1, and GLI2 expression levels positively correlated with the malignant phenotypes of tumor cells.

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Acknowledgements

We thank Mrs. Kaoru Tsuboi and Ms. Megumi Ogo for their technical assistance. This work was supported by Research Project Grants from Kawasaki Medical School (28-1 and 29-1) and the Ministry of Education, Culture, Sports, Science, and Technology, Japan (17K10566).

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Authors and Affiliations

  1. Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan

    Junichi Kurebayashi, Yoshikazu Koike, Yusuke Ohta, Wataru Saitoh & Emi Kishino

  2. Department of Pathology 2, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan

    Naoki Kanomata

Authors
  1. Junichi Kurebayashi
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  2. Naoki Kanomata
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  3. Yoshikazu Koike
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  4. Yusuke Ohta
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  5. Wataru Saitoh
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  6. Emi Kishino
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Corresponding author

Correspondence to Junichi Kurebayashi.

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Conflict of interest

J. Kurebayashi received advisory/consultation fees and research funding from Takeda Pharmaceutical and Chugai Co. J. Kurebayashi received research funding from Takeda Pharmaceutical, Eisai, and Chugai Co. The other authors have no conflict of interest to declare.

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Supplementary material 1 (XLSX 17 KB)

12282_2018_884_MOESM2_ESM.pptx

Figure S1 RFS curves of younger patients (younger than or equal to 49 years old) vs. older patients (older than or equal to 50 years old) (A) and patients with positive lymphatic vs. negative invasion (B). Figure S2 Correlations among expression levels of SHH, GLI1, and GLI2 and clinicopathological factors, histological grades, and HER2 IHC scores in breast cancer tissues. A. The relationship between SHH histoscores and histological grades, B. The relationship between GLI1 histoscores and histological grades, C. The relationship between GLI2 histoscores and histological grades, and D. The relationship between SHH histoscores and HER2 IHC scores. *P < 0.05 versus the histological grade I for A, B, and C, **P  < 0.01 versus the histological grade I for A, B, and C, **P < 0.01 for D. Figure S3 Correlations between SHH and GLI2 histoscores and IHC intrinsic subtypes in breast cancer tissues. A. Relationships among SHH histoscores and IHC intrinsic subtypes, and B. Relationships between GLI2 histoscores and IHC intrinsic subtypes. *P < 0.05 versus the HR-positive/HER2-negative subtype, and **P < 0.01 versus the HR-positive/HER2-negative subtype (PPTX 70 KB)

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Kurebayashi, J., Kanomata, N., Koike, Y. et al. Comprehensive immunohistochemical analyses on expression levels of hedgehog signaling molecules in breast cancers. Breast Cancer 25, 759–767 (2018). https://doi.org/10.1007/s12282-018-0884-2

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  • DOI: https://doi.org/10.1007/s12282-018-0884-2

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