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SGLT1 as an adverse prognostic factor in invasive ductal carcinoma of the breast

  • Original Laboratory Investigation
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Sodium/glucose cotransporter (SGLT) 1 and 2 expression in carcinoma cells was recently examined, but their association with the clinicopathological factors of the patients and their biological effects on breast carcinoma cells have remained remain virtually unknown. Therefore, in this study, we explored the expression status of SGLT1 and SGLT2 in breast cancer patients and examined the effects of SGLT1 inhibitors on breast carcinoma cells in vitro.

Methods

SGLT1 and SGLT2 were immunolocalized and we first correlated the findings with clinicopathological factors of the patients. We then administered mizagliflozin and KGA-2727, SGLT1 specific inhibitors to MCF-7 and MDA-MB-468 breast carcinoma cell lines, and their growth-inhibitory effects were examined. Protein arrays were then used to further explore their effects on the growth factors.

Results

The SGLT1 high group had significantly worse clinical outcome including both overall survival and disease-free survival than low group. SGLT2 status was not significantly correlated with clinical outcome of the patients. Both mizagliflozin and KGA-2727 inhibited the growth of breast cancer cell lines. Of particular interest, mizagliflozin inhibited the proliferation of MCF-7 cells, even under very low glucose conditions. Mizagliflozin downregulated vascular endothelial growth factor receptor 2 phosphorylation.

Conclusion

High SGLT1 expression turned out as an adverse clinical prognostic factor in breast cancer patient. This is the first study demonstrating that SGLT1 inhibitors suppressed breast carcinoma cell proliferation. These results indicated that SGLT1 inhibitors could be used as therapeutic agents for breast cancer patients with aggressive biological behaviors.

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Data availability

All data generated or analyzed during this study are included in this article and its supplementary information files.

Abbreviations

ATCC:

American type culture collection

DAB:

3,3′-Diaminobenzidine

DFS:

Disease-free survival

DMSO:

Dimethyl sulfoxide

EGFR:

Epidermal growth factor receptor

ER:

Estrogen receptor

DCIS:

Ductal carcinoma in situ

HER2:

Human epidermal growth factor receptor 2

IDC:

Invasive ductal carcinoma

GLUT:

Glucose transporters

OS:

Overall survival

PET:

Positron emission tomography

PI3K:

Phosphoinositide-3 kinase

PgR:

Progesterone receptor

PVDF:

Polyvinylidene difluoride

TBS-T:

Tris-buffered saline containing Tween-20

SGLT:

Sodium/glucose cotransporters

VEGFR-2:

Vascular endothelial growth factor receptor-2

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Acknowledgements

We thank Akiko Morohashi and Katsuhiko Ono for the excellent technical assistance.

Funding

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

    Satoko Tsunokake & Takanori Ishida

  2. Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

    Erina Iwabuchi & Takashi Suzuki

  3. Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

    Yasuhiro Miki, Yoshiaki Onodera, Hironobu Sasano & Takashi Suzuki

  4. Department of Breast Surgery, Hachinohe City Hospital, Hachinohe, Aomori, Japan

    Ayako Kanai

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  1. Satoko Tsunokake
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Contributions

ST and YO performed the experiments. EI and YM designed the study. ST, AK, and TI interpreted the clinical data. ST wrote the manuscript. TS and HS reviewed and edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Erina Iwabuchi.

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The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

This study was approved by the Medical Ethics Committee of Tohoku University Graduate School of Medicine (Reception No. 2020–1-942).

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Informed consent was obtained from all individual participants included in the study.

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Tsunokake, S., Iwabuchi, E., Miki, Y. et al. SGLT1 as an adverse prognostic factor in invasive ductal carcinoma of the breast. Breast Cancer Res Treat 201, 499–513 (2023). https://doi.org/10.1007/s10549-023-07024-9

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