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

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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.

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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

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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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Authors and Affiliations

  1. Department of Surgery, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Jin Cheon Kim, Jong Han Yu, Yoon Kyung Cho, Choon Sik Jung & Sei Hyun Ahn

  2. Institute of Innovative Cancer Research, Asan Medical Center, 86 Asanbyeongwon-gil, Sonpa-gu, Seoul, 138-736, Republic of Korea

    Jin Cheon Kim, Jong Han Yu, Yoon Kyung Cho, Choon Sik Jung, Sei Hyun Ahn, Yong Sung Kim & Dong-Hyung Cho

  3. Department of Pathology, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Gyungyub Gong

  4. Graduate School of East–West Medical Science, Kyung Hee University, Gyeonggi-Do, Republic of Korea

    Dong-Hyung Cho

  5. Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Eoeun-dong Yuseong-ku, Daejeon, 305-333, Republic of Korea

    Yong Sung Kim

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  1. Jin Cheon Kim
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Correspondence to Jin Cheon Kim or Dong-Hyung Cho.

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Kim, J.C., Yu, J.H., Cho, Y.K. et al. Expression of SPRR3 is associated with tumor cell proliferation in less advanced stages of breast cancer. Breast Cancer Res Treat 133, 909–916 (2012). https://doi.org/10.1007/s10549-011-1868-5

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  • DOI: https://doi.org/10.1007/s10549-011-1868-5

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