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


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.


Breast cancer SPRR3 Tumorigenesis p53 



Serine/threonine protein kinase


Breast cancer HR


Confidence interval


Colorectal cancer


Disease-free survival


Estrogen receptor


Esophageal squamous cell cancer


Human epidermal growth factor receptor 2


Hazard ratio


Mitogen-activated protein kinase


Murine double minute 2


MAPK/extracellular signal-regulated kinase


Odds ratio


Overall survival


Phosphatidylinositol 3′ kinase


Progesterone receptor


Rapidly accelerated fibrosarcoma


Reporting recommendations for tumor marker prognostic studies


Small interfering ribonucleic acid


Small proline rich repeat protein 3


Triple negative BC



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.


  1. 1.
    Ko SS, Korean Breast Cancer Society (2005) Chronological changing patterns of clinical characteristics of Korean breast cancer patients during 10 years (1996–2006) using nationwide breast cancer registration on-line program: biannual update. J Surg Oncol 98:318–323CrossRefGoogle Scholar
  2. 2.
    Parkin DM, Bray FI, Devesa SS (2001) Cancer burden in the year 2000. The global picture. Eur J Cancer 37:S4–S66PubMedCrossRefGoogle Scholar
  3. 3.
    Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J, Investigators FinHer Study (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809–820PubMedCrossRefGoogle Scholar
  4. 4.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD, Adjuvant Herceptin, (HERA) Trial Study Team (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672PubMedCrossRefGoogle Scholar
  5. 5.
    Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684PubMedCrossRefGoogle Scholar
  6. 6.
    Gutierrez C, Schiff R (2011) HER2: biology, detection, and clinical implications. Arch Pathol Lab Med 135:55–62PubMedGoogle Scholar
  7. 7.
    Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN (2009) The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 14:320–368PubMedCrossRefGoogle Scholar
  8. 8.
    López-Knowles E, O’Toole SA, McNeil CM, Millar EK, Qiu MR, Crea P, Daly RJ, Musgrove EA, Sutherland RL (2010) PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int J Cancer 126:1121–1131PubMedGoogle Scholar
  9. 9.
    Castaneda CA, Cortes-Funes H, Gomez HL, Ciruelos EM (2010) The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer. Cancer Metastasis Rev 29:751–759PubMedCrossRefGoogle Scholar
  10. 10.
    Lacroix M, Toillon RA, Leclercq G (2006) p53 and breast cancer, an update. Endocr Relat Cancer 13:293–325PubMedCrossRefGoogle Scholar
  11. 11.
    Tesfaigzi J, Th’ng J, Hotchkiss JA, Harkema JR, Wright PS (1996) A small proline-rich protein, SPRR1, is upregulated early during tobacco smoke-induced squamous metaplasia in rat nasal epithelia. Am J Respir Cell Mol Biol 14:478–486PubMedGoogle Scholar
  12. 12.
    De Heller-Milev M, Huber M, Panizzon R, Hohl D (2000) Expression of small proline rich proteins in neoplastic and inflammatory skin diseases. Br J Dermatol 143:733–740PubMedCrossRefGoogle Scholar
  13. 13.
    Kim JC, Kim SY, Roh SA, Cho DH, Kim DD, Kim JH, Kim YS (2008) Gene expression profiling: canonical molecular changes and clinicopathological features in sporadic colorectal cancers. World J Gastroenterol 14:6662–6672PubMedCrossRefGoogle Scholar
  14. 14.
    Cho DH, Jo YK, Roh SA, Na YS, Kim TW, Jang SJ, Kim YS, Kim JC (2010) Upregulation of SPRR3 promotes colorectal tumorigenesis. Mol Med 16:271–277PubMedCrossRefGoogle Scholar
  15. 15.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97:1180–1184PubMedCrossRefGoogle Scholar
  16. 16.
    Kimchi ET, Posner MC, Park JO, Darga TE, Kocherginsky M, Karrison T, Hart J, Smith KD, Mezhir JJ, Weichselbaum RR, Khodarev NN (2005) Progression of Barrett’s metaplasia to adenocarcinoma is associated with the suppression of the transcriptional programs of epidermal differentiation. Cancer Res 65:3146–3154PubMedGoogle Scholar
  17. 17.
    Luthra R, Wu TT, Luthra MG, Izzo J, Lopez-Alvarez E, Zhang L, Bailey J, Lee JH, Bresalier R, Rashid A, Swisher SG, Ajani JA (2006) Gene expression profiling of localized esophageal carcinomas: association with pathologic response to preoperative chemoradiation. J Clin Oncol 24:259–267PubMedCrossRefGoogle Scholar
  18. 18.
    Kimos MC, Wang S, Borkowski A, Yang GY, Yang CS, Perry K, Olaru A, Deacu E, Sterian A, Cottrell J, Papadimitriou J, Sisodia L, Selaru FM, Mori Y, Xu Y, Yin J, Abraham JM, Meltzer SJ (2004) Esophagin and proliferating cell nuclear antigen (PCNA) are biomarkers of human esophageal neoplastic progression. Int J Cancer 111:415–417PubMedCrossRefGoogle Scholar
  19. 19.
    Yarden Y (2001) Biology of HER2 and its importance in breast cancer. Oncology 61(suppl 2):1–13PubMedCrossRefGoogle Scholar
  20. 20.
    Pal SK, Childs BH, Pegram M (2011) Triple negative breast cancer: unmet medical needs. Breast Cancer Res Treat 125:627–636PubMedCrossRefGoogle Scholar
  21. 21.
    Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13:4429–4434PubMedCrossRefGoogle Scholar
  22. 22.
    Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789PubMedCrossRefGoogle Scholar
  23. 23.
    Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC (2001) Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 3:245–252PubMedCrossRefGoogle Scholar
  24. 24.
    Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC (2001) HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 3:973–982PubMedCrossRefGoogle Scholar
  25. 25.
    Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, Masuyama N, Gotoh Y (2002) Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem 277:21843–21850PubMedCrossRefGoogle Scholar
  26. 26.
    Agrawal A, Yang J, Murphy RF, Agrawal DK (2006) Regulation of the p14ARF-Mdm2–p53 pathway: an overview in breast cancer. Exp Mol Pathol 81:115–122PubMedCrossRefGoogle Scholar
  27. 27.
    Tartaglia M, Gelb BD (2010) Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms. Ann NY Acad Sci 1214:99–121PubMedCrossRefGoogle Scholar
  28. 28.
    McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA (2007) Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 1773:1263–1284PubMedCrossRefGoogle Scholar

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

Personalised recommendations