Top

Published in:

01-07-2012 | Preclinical Study

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

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

Published in: Breast Cancer Research and Treatment | Issue 1/2012

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.

Available only for authorised users

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

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

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

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

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):274–285PubMedCrossRef

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):380–386PubMedCrossRef

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):7384–7391PubMedCrossRef

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):3064–3068PubMedCrossRef

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):707–715PubMedCrossRef

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):6049–6054PubMedCrossRef

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):3348–3353PubMedCrossRef

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):595–602PubMedCrossRef

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):2687–2693PubMedCrossRef

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):340–348PubMedCrossRef

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):3274–3279PubMedCrossRef

16.

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

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):1591–1597PubMed

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):11–15PubMedCrossRef

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):353–360PubMedCrossRef

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):2649–2657PubMed

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):1575–1585PubMedCrossRef

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):3248–3255PubMedCrossRef

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):903–912PubMedCrossRef

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):2952–2960PubMedCrossRef

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):403–409PubMedCrossRef

26.

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

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):555–569PubMedCrossRef

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):69–77PubMedCrossRef

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):421–430PubMedCrossRef

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):4234–4241PubMedCrossRef

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):359–377PubMedCrossRef

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):149–157PubMedCrossRef

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):871–875PubMedCrossRef

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):4353–4357PubMed

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 8:308PubMedCrossRef

Title: 14-3-3σ expression is associated with poor pathological complete response to neoadjuvant chemotherapy in human breast cancers
Authors: Yukiko Nakamura
Kazuteru Oshima
Yasuto Naoi
Takahiro Nakayama
Seung Jin Kim
Kenzo Shimazu
Atsushi Shimomura
Naomi Maruyama
Yasuhiro Tamaki
Shinzaburo Noguchi
Publication date: 01-07-2012
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-012-1976-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2012

Stromal–epithelial interactions modulate cross-talk between prolactin receptor and HER2/Neu in breast cancer

Quality of life over time in women diagnosed with ductal carcinoma in situ, early-stage invasive breast cancer, and age-matched controls

The fibroblast growth factor receptor 1 (FGFR1), a marker of response to chemoradiotherapy in breast cancer?

The miRNA-200 family and miRNA-9 exhibit differential expression in primary versus corresponding metastatic tissue in breast cancer

Overexpression of a novel cell cycle regulator ecdysoneless in breast cancer: a marker of poor prognosis in HER2/neu-overexpressing breast cancer patients

Final results of a multicenter phase II clinical trial evaluating the activity of single-agent lapatinib in patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study

Keynote webinar | Spotlight on antibody–drug conjugates in cancer