Skip to main content

Advertisement

SpringerLink
Log in

14-3-3σ expression is associated with poor pathological complete response to neoadjuvant chemotherapy in human breast cancers

  • Preclinical Study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

14-3-3σ is a tumor suppressor gene induced by p53 in response to DNA damage and reportedly associated with resistance to chemotherapy. The aim of this study was to investigate whether 14-3-3σ expression is also associated with resistance to neoadjuvant chemotherapy consisting of paclitaxel followed by 5-FU/epirubicin/cyclophosphamide (P-FEC) in human breast cancer patients. A total of 123 primary breast cancer patients treated with neoadjuvant chemotherapy (P-FEC) were included in this study. Immunohistochemistry of 14-3-3σ and p53 as well as direct sequencing of TP53 were performed using the tumor biopsy samples obtained prior to neoadjuvant chemotherapy. Thirty-eight of the tumors (31%) were positive for 14-3-3σ. There was no significant association between 14-3-3σ expression and TP53 mutation or p53 expression. However, 14-3-3σ expression showed a significantly (P = 0.009) negative association with pathological complete response (pCR) to P-FEC, and multivariate analysis demonstrated that only 14-3-3σ (P = 0.015) and estrogen receptor (P = 0.021) were significantly and independently associated with pCR. The combination of 14-3-3σ expression and TP53 mutation status had an additive negative effect on pCR, i.e., pCR rates were 45.5% for 14-3-3σ negative/TP53 mutant tumors, 24.6% for 14-3-3σ negative/TP53 wild tumors, 23.1% for 14-3-3σ positive/TP53 mutant tumors, and 0% for 14-3-3σ positive/TP53 wild tumors. These results demonstrate that 14-3-3σ expression is significantly associated with resistance to P-FEC and this association is independent of other biological markers. The combination of 14-3-3σ expression and TP53 mutation status has an additively negative effect on the response to P-FEC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Mhawech P (2005) 14-3-3 proteins—an update. Cell Res 15(4):228–236

    Article  PubMed  CAS  Google Scholar 

  2. Horie-Inoue K, Inoue S (2006) Epigenetic and proteolytic inactivation of 14-3-3sigma in breast and prostate cancers. Semin Cancer Biol 16(3):235–239

    Article  PubMed  CAS  Google Scholar 

  3. Lee MH, Lozano G (2006) Regulation of the p53-MDM2 pathway by 14-3-3 sigma and other proteins. Semin Cancer Biol 16(3):225–234

    Article  PubMed  CAS  Google Scholar 

  4. Hermeking H, Benzinger A (2006) 14-3-3 proteins in cell cycle regulation. Semin Cancer Biol 16(3):183–192

    Article  PubMed  CAS  Google Scholar 

  5. Simpson PT, Gale T, Reis-Filho JS, Jones C, Parry S, Steele D, Cossu A, Budroni M, Palmieri G, Lakhani SR (2004) Distribution and significance of 14-3-3sigma, a novel myoepithelial marker, in normal, benign, and malignant breast tissue. J Pathol 202(3):274–285

    Article  PubMed  CAS  Google Scholar 

  6. Mirza S, Sharma G, Parshad R, Srivastava A, Gupta SD, Ralhan R (2010) Clinical significance of Stratifin, ERalpha and PR promoter methylation in tumor and serum DNA in Indian breast cancer patients. Clin Biochem 43(4–5):380–386

    Article  PubMed  CAS  Google Scholar 

  7. Ito K, Suzuki T, Akahira J, Sakuma M, Saitou S, Okamoto S, Niikura H, Okamura K, Yaegashi N, Sasano H, Inoue S (2005) 14-3-3sigma in endometrial cancer—a possible prognostic marker in early-stage cancer. Clin Cancer Res 11(20):7384–7391

    Article  PubMed  CAS  Google Scholar 

  8. Cheng L, Pan CX, Zhang JT, Zhang S, Kinch MS, Li L, Baldridge LA, Wade C, Hu Z, Koch MO, Ulbright TM, Eble JN (2004) Loss of 14-3-3sigma in prostate cancer and its precursors. Clin Cancer Res 10(9):3064–3068

    Article  PubMed  CAS  Google Scholar 

  9. Nakayama H, Sano T, Motegi A, Oyama T, Nakajima T (2005) Increasing 14-3-3 sigma expression with declining estrogen receptor alpha and estrogen-responsive finger protein expression defines malignant progression of endometrial carcinoma. Pathol Int 55(11):707–715

    Article  PubMed  CAS  Google Scholar 

  10. Ferguson AT, Evron E, Umbricht CB, Pandita TK, Chan TA, Hermeking H, Marks JR, Lambers AR, Futreal PA, Stampfer MR, Sukumar S (2000) High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer. Proc Natl Acad Sci USA 97(11):6049–6054

    Article  PubMed  CAS  Google Scholar 

  11. Umbricht CB, Evron E, Gabrielson E, Ferguson A, Marks J, Sukumar S (2001) Hypermethylation of 14-3-3 sigma (stratifin) is an early event in breast cancer. Oncogene 20(26):3348–3353

    Article  PubMed  CAS  Google Scholar 

  12. Simooka H, Oyama T, Sano T, Horiguchi J, Nakajima T (2004) Immunohistochemical analysis of 14-3-3 sigma and related proteins in hyperplastic and neoplastic breast lesions, with particular reference to early carcinogenesis. Pathol Int 54(8):595–602

    Article  PubMed  CAS  Google Scholar 

  13. Akahira J, Sugihashi Y, Suzuki T, Ito K, Niikura H, Moriya T, Nitta M, Okamura H, Inoue S, Sasano H, Okamura K, Yaegashi N (2004) Decreased expression of 14-3-3 sigma is associated with advanced disease in human epithelial ovarian cancer: its correlation with aberrant DNA methylation. Clin Cancer Res 10(8):2687–2693

    Article  PubMed  CAS  Google Scholar 

  14. Mhawech P, Benz A, Cerato C, Greloz V, Assaly M, Desmond JC, Koeffler HP, Lodygin D, Hermeking H, Herrmann F, Schwaller J (2005) Downregulation of 14-3-3sigma in ovary, prostate and endometrial carcinomas is associated with CpG island methylation. Mod Pathol 18(3):340–348

    Article  PubMed  CAS  Google Scholar 

  15. Perathoner A, Pirkebner D, Brandacher G, Spizzo G, Stadlmann S, Obrist P, Margreiter R, Amberger A (2005) 14-3-3sigma expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients. Clin Cancer Res 11(9):3274–3279

    Article  PubMed  CAS  Google Scholar 

  16. Neupane D, Korc M (2008) 14-3-3sigma Modulates pancreatic cancer cell survival and invasiveness. Clin Cancer Res 14(23):7614–7623

    Article  PubMed  CAS  Google Scholar 

  17. Tanaka K, Hatada T, Kobayashi M, Mohri Y, Tonouchi H, Miki C, Nobori T, Kusunoki M (2004) The clinical implication of 14-3-3 sigma expression in primary gastrointestinal malignancy. Int J Oncol 25(6):1591–1597

    PubMed  CAS  Google Scholar 

  18. Holm R, Ali T, Svendsrud DH, Nesland JM, Kristensen GB, Lyng H (2009) Expression of 14-3-3sigma in cervical squamous cell carcinomas: relationship with clinical outcome. Oncol Rep 22(1):11–15

    Article  PubMed  CAS  Google Scholar 

  19. Nakajima T, Shimooka H, Weixa P, Segawa A, Motegi A, Jian Z, Masuda N, Ide M, Sano T, Oyama T, Tsukagoshi H, Hamanaka K, Maeda M (2003) Immunohistochemical demonstration of 14-3-3 sigma protein in normal human tissues and lung cancers, and the preponderance of its strong expression in epithelial cells of squamous cell lineage. Pathol Int 53(6):353–360

    Article  PubMed  CAS  Google Scholar 

  20. Logsdon CD, Simeone DM, Binkley C, Arumugam T, Greenson JK, Giordano TJ, Misek DE, Kuick R, Hanash S (2003) Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer. Cancer Res 63(10):2649–2657

    PubMed  CAS  Google Scholar 

  21. Guweidhi A, Kleeff J, Giese N, El Fitori J, Ketterer K, Giese T, Buchler MW, Korc M, Friess H (2004) Enhanced expression of 14-3-3sigma in pancreatic cancer and its role in cell cycle regulation and apoptosis. Carcinogenesis 25(9):1575–1585

    Article  PubMed  CAS  Google Scholar 

  22. Liu Y, Liu H, Han B, Zhang JT (2006) Identification of 14-3-3sigma as a contributor to drug resistance in human breast cancer cells using functional proteomic analysis. Cancer Res 66(6):3248–3255

    Article  PubMed  CAS  Google Scholar 

  23. Han B, Xie H, Chen Q, Zhang JT (2006) Sensitizing hormone-refractory prostate cancer cells to drug treatment by targeting 14-3-3sigma. Mol Cancer Ther 5(4):903–912

    Article  PubMed  CAS  Google Scholar 

  24. Sinha P, Hutter G, Kottgen E, Dietel M, Schadendorf D, Lage H (1999) Increased expression of epidermal fatty acid binding protein, cofilin, and 14-3-3-sigma (stratifin) detected by two-dimensional gel electrophoresis, mass spectrometry and microsequencing of drug-resistant human adenocarcinoma of the pancreas. Electrophoresis 20(14):2952–2960

    Article  PubMed  CAS  Google Scholar 

  25. Gehrmann ML, Fenselau C, Hathout Y (2004) Highly altered protein expression profile in the adriamycin resistant MCF-7 cell line. J Proteome Res 3(3):403–409

    Article  PubMed  CAS  Google Scholar 

  26. Gehrmann ML, Hathout Y, Fenselau C (2004) Evaluation of metabolic labeling for comparative proteomics in breast cancer cells. J Proteome Res 3(5):1063–1068

    Article  PubMed  CAS  Google Scholar 

  27. Moreira JM, Ohlsson G, Rank FE, Celis JE (2005) Down-regulation of the tumor suppressor protein 14-3-3sigma is a sporadic event in cancer of the breast. Mol Cell Proteomics 4(4):555–569

    Article  PubMed  CAS  Google Scholar 

  28. Iwamoto T, Yamamoto N, Taguchi T, Tamaki Y, Noguchi S (2011) BRCA1 promoter methylation in peripheral blood cells is associated with increased risk of breast cancer with BRCA1 promoter methylation. Breast Cancer Res Treat 129(1):69–77

    Article  PubMed  CAS  Google Scholar 

  29. Shimomura A, Miyoshi Y, Taguchi T, Tamaki Y, Noguchi S (2009) Association of loss of BRCA1 expression with centrosome aberration in human breast cancer. J Cancer Res Clin Oncol 135(3):421–430

    Article  PubMed  CAS  Google Scholar 

  30. Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, Tamaki Y, Noguchi S (2009) Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res 15(12):4234–4241

    Article  PubMed  CAS  Google Scholar 

  31. Bloom HJ, Richardson WW (1957) Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer 11(3):359–377

    Article  PubMed  CAS  Google Scholar 

  32. Oshima K, Naoi Y, Kishi K, Nakamura Y, Iwamoto T, Shimazu K, Nakayama T, Kim SJ, Baba Y, Tamaki Y, Noguchi S (2011) Gene expression signature of TP53 but not its mutation status predicts response to sequential paclitaxel and 5-FU/epirubicin/cyclophosphamide in human breast cancer. Cancer Lett 307(2):149–157

    Article  PubMed  CAS  Google Scholar 

  33. Urano T, Saito T, Tsukui T, Fujita M, Hosoi T, Muramatsu M, Ouchi Y, Inoue S (2002) Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth. Nature 417(6891):871–875

    Article  PubMed  CAS  Google Scholar 

  34. Suzuki H, Itoh F, Toyota M, Kikuchi T, Kakiuchi H, Imai K (2000) Inactivation of the 14-3-3 sigma gene is associated with 5′ CpG island hypermethylation in human cancers. Cancer Res 60(16):4353–4357

    PubMed  CAS  Google Scholar 

  35. Wang Z, Trope CG, Suo Z, Troen G, Yang G, Nesland JM, Holm R (2008) The clinicopathological and prognostic impact of 14-3-3 sigma expression on vulvar squamous cell carcinomas. BMC Cancer 8:308

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by a grant for the Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare, Japan.

Conflict of interest

Research grants: S. Noguchi from Pfizer and Bristol-Myers Squibb., Honoraria: S. Noguchi from Pfizer and Bristol-Myers Squibb, S.J. Kim from Bristol-Myers, and T. Nakayama from Pfizer and Bristol-Myers.

Author information

Authors and Affiliations

  1. Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, 2-2-E10 Yamadaoka, Suita-shi, Osaka, 565-0871, Japan

    Yukiko Nakamura, Kazuteru Oshima, Yasuto Naoi, Takahiro Nakayama, Seung Jin Kim, Kenzo Shimazu, Atsushi Shimomura, Naomi Maruyama, Yasuhiro Tamaki & Shinzaburo Noguchi

Authors
  1. Yukiko Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuteru Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasuto Naoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takahiro Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seung Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kenzo Shimazu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Atsushi Shimomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naomi Maruyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yasuhiro Tamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shinzaburo Noguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shinzaburo Noguchi.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1 (DOC 62 kb)

10549_2012_1976_MOESM2_ESM.jpg

Supplementary Fig. 1 . 14-3-3σ promoter hypermethylation and 14-3-3σ protein expression. Immunohistochemical staining results for six tumors with 14-3-3σ promoter hypermethylation. M, amplification with methylated primers; U, amplification with unmethylated primers. Scale bars: 200 μm. Marker: 200 bp DNA ladder marker. (JPG 147 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nakamura, Y., Oshima, K., Naoi, Y. et al. 14-3-3σ expression is associated with poor pathological complete response to neoadjuvant chemotherapy in human breast cancers. Breast Cancer Res Treat 134, 229–236 (2012). https://doi.org/10.1007/s10549-012-1976-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-012-1976-x

Keywords

Search

Navigation