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High mobility group A1 (HMGA1) protein and gene expression correlate with ER-negativity and poor outcomes in breast cancer

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Abstract

Purpose

The high mobility group A1 (HMGA1) chromatin remodeling protein is required for metastatic progression and cancer stem cell properties in preclinical breast cancer models, although its role in breast carcinogenesis has remained unclear. To investigate HMGA1 in primary breast cancer, we evaluated immunoreactivity score (IRS) in tumors from a large cohort of Asian women; HMGA1 gene expression was queried from two independent Western cohorts.

Methods

HMGA1 IRS was generated from breast tumors in Korean women as the product of staining intensity (weak = 1, moderate = 2, strong = 3) and percent positive cells (< 5% = 0, 5–30% = 1, 30–60% = 2, > 60% = 3), and stratified into three groups: low (< 3), intermediate (3–6), high (> 6). We assessed HMGA1 and estrogen receptor (ESR1) gene expression from two large databases (TCGA, METABRIC). Overall survival was ascertained from the METABRIC cohort.

Results

Among 540 primary tumors from Korean women (181 ER-negative, 359 ER-positive), HMGA1 IRS was < 3 in 89 (16.5%), 3–6 in 215 (39.8%), and > 6 in 236 (43.7%). High HMGA1 IRS was associated with estrogen receptor (ER)-negativity (χ2 = 12.07; P = 0.002) and advanced nuclear grade (χ2 = 12.83; P = 0.012). In two large Western cohorts, the HMGA1 gene was overexpressed in breast cancers compared to non-malignant breast tissue (P < 0.0001), including Asian, African American, and Caucasian subgroups. HMGA1 was highest in ER-negative tumors and there was a strong inverse correlation between HMGA1 and ESR1 gene expression (Pearson r = − 0.60, P < 0.0001). Most importantly, high HMGA1 predicted decreased overall survival (P < 0.0001) for all women with breast cancer and further stratified ER-positive tumors into those with inferior outcomes.

Conclusions

Together, our results suggest that HMGA1 contributes to estrogen-independence, tumor progression, and poor outcomes. Moreover, further studies are warranted to determine whether HMGA1 could serve as a prognostic marker and therapeutic target for women with breast cancer.

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Funding

This work was funded by NIH R21 CA2149550, NIH R01 DK102943, NIH R01 HL145780, NIH R01 CA232741, the Cindy Rosencrans Fund for Metastatic Triple Negative Breast Cancer Research, the Safeway Breast Cancer Award, and the AVON Breast Cancer Fund (to L.M.S. Resar). This work was also supported by the Medical Research Center Program (2015R1A5A2009124) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (to Y.K. Bae). The authors wish to thank these agencies for their generous support.

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Author notes

  1. Mikhail Gorbounov and Neil M. Carleton are co-first authors who contributed equally to this work. Young Kyung Bae and Linda M. S. Resar are senior authors who contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Mikhail Gorbounov, Rebecca J. Asch-Kendrick, Lisa Rooper, Lionel Chia, Ashley Cimino-Mathews, Alan Meeker & Linda M. S. Resar

  2. Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Neil M. Carleton, Alan Meeker & Robert W. Veltri

  3. Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Lingling Xian, Lionel Chia & Linda M. S. Resar

  4. Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Lionel Chia & Linda M. S. Resar

  5. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Ashley Cimino-Mathews, Leslie Cope, Alan Meeker, Vered Stearns & Linda M. S. Resar

  6. Department of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Leslie Cope

  7. Department of Pathology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu, 42415, South Korea

    Young Kyung Bae

  8. Institute for Cellular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Linda M. S. Resar

  9. The Johns Hopkins University School of Medicine, Ross Research Building, Room 1025, 720 Rutland Ave, Baltimore, MD, 21205, USA

    Linda M. S. Resar

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  1. Mikhail Gorbounov
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  2. Neil M. Carleton
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  6. Lionel Chia
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  11. Robert W. Veltri
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  12. Young Kyung Bae
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  13. Linda M. S. Resar
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Correspondence to Young Kyung Bae or Linda M. S. Resar.

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Gorbounov, M., Carleton, N.M., Asch-Kendrick, R.J. et al. High mobility group A1 (HMGA1) protein and gene expression correlate with ER-negativity and poor outcomes in breast cancer. Breast Cancer Res Treat 179, 25–35 (2020). https://doi.org/10.1007/s10549-019-05419-1

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