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Breast Cancer Research and Treatment

, Volume 133, Issue 3, pp 909–916 | Cite as

Expression of SPRR3 is associated with tumor cell proliferation in less advanced stages of breast cancer

  • Jin Cheon KimEmail author
  • Jong Han Yu
  • Yoon Kyung Cho
  • Choon Sik Jung
  • Sei Hyun Ahn
  • Gyungyub Gong
  • Yong Sung Kim
  • Dong-Hyung ChoEmail author
Preclinical Study

Abstract

Small proline rich repeat protein 3 (SPRR3), a member of the SPRR family of cornified envelope precursor proteins, is a marker for terminal squamous cell differentiation. Previously, this laboratory showed that SPRR3 is strongly upregulated in colorectal tumors, and is involved in the tumorigenesis. The current study was performed to investigate the expression status and effect of SPRR3 in breast cancers (BCs). SPRR3 expression was examined by immunohistochemistry in 241 tumor samples from BC patients. SPRR3 was overexpressed in more than half of all BC samples. SPRR3 overexpression was significantly associated with less advanced stage (0–1 vs. II–III) and the absence of lymph node metastasis (P = 0.004 and 0.013, respectively). HER2/neu overexpression was closely correlated with SPRR3 overexpression in a multivariate analysis (OR, 3.23, P = 0.017). To assess the influence of SPRR3 on cell proliferation and related signaling pathways, SPRR3-transfected clones from the SPRR3-negative T-47D human BC cell line were generated. Among the total of six SPRR3-overexpressing clones, five showed marked proliferation compared with SPRR3-nonexpressing control cells from day 3 of culture (P < 0.001). The SPRR3-overexpressing BC clones showed increased phosphorylation of AKT and MDM2, p21 overexpression, and p53 downregulation. Furthermore, phosphorylation of MEK and MAPK was markedly increased. This study demonstrates that SPRR3 promotes BC cell proliferation by enhancing p53 degradation via the AKT and MAPK pathways and is, therefore, a potential novel therapeutic target for less advanced stages of BC.

Keywords

Breast cancer SPRR3 Tumorigenesis p53 

Abbreviations

AKT

Serine/threonine protein kinase

BC

Breast cancer HR

CI

Confidence interval

CRC

Colorectal cancer

DFS

Disease-free survival

ER

Estrogen receptor

ESCC

Esophageal squamous cell cancer

HER2/neu

Human epidermal growth factor receptor 2

HR

Hazard ratio

MAPK

Mitogen-activated protein kinase

MDM2

Murine double minute 2

MEK

MAPK/extracellular signal-regulated kinase

OR

Odds ratio

OS

Overall survival

PI3K

Phosphatidylinositol 3′ kinase

PR

Progesterone receptor

RAF

Rapidly accelerated fibrosarcoma

REMARK

Reporting recommendations for tumor marker prognostic studies

siRNA

Small interfering ribonucleic acid

SPRR3

Small proline rich repeat protein 3

TNBC

Triple negative BC

Notes

Acknowledgments

This study was supported by grants to J.C.K. from the Asan Institute for Life Sciences (2011-069), the Korea Health 21 R&D Project (A062254) and the Center for Development and the Commercialization of Anti-Cancer Therapeutics (A102059), Ministry of Health, Welfare, and Family Affairs, Republic of Korea.

Conflict of interest

The authors declare that they have no competing interests.

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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Jin Cheon Kim
    • 1
    • 2
    Email author
  • Jong Han Yu
    • 1
    • 2
  • Yoon Kyung Cho
    • 1
    • 2
  • Choon Sik Jung
    • 1
    • 2
  • Sei Hyun Ahn
    • 1
    • 2
  • Gyungyub Gong
    • 3
  • Yong Sung Kim
    • 5
    • 2
  • Dong-Hyung Cho
    • 4
    • 2
    Email author
  1. 1.Department of SurgeryUniversity of Ulsan College of MedicineSeoulRepublic of Korea
  2. 2.Institute of Innovative Cancer ResearchSeoulRepublic of Korea
  3. 3.Department of PathologyUniversity of Ulsan College of MedicineSeoulRepublic of Korea
  4. 4.Graduate School of East–West Medical ScienceKyung Hee UniversityGyeonggi-DoRepublic of Korea
  5. 5.Medical Genomics Research CenterKorea Research Institute of Bioscience and BiotechnologyDaejeonRepublic of Korea

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