Research Article| Volume 45, ISSUE 7, P1274-1281, May 2009

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Annexins in human breast cancer: Possible predictors of pathological response to neoadjuvant chemotherapy

Published:January 27, 2009DOI:


      Neoadjuvant chemotherapy is used in women who have large or locally advanced breast cancers. However, up to 70% of women who receive neoadjuvant chemotherapy fail to achieve a complete pathological response in their primary tumour (a surrogate marker of long-term survival). Five proteins, previously identified to be linked with chemoresistance in our in vitro experiments, were identified histochemically in pre-treatment core needle biopsies from 40 women with large or locally advanced breast cancers. Immunohistochemical staining with the five proteins showed no single protein to be a predictor of response to chemotherapy. However, pre-treatment breast cancer specimens that were annexin-A2 positive but annexin-A1 negative correlated with a poor pathological response (p = 0.04, Fisher’s exact test). The mechanisms by which annexins confer chemoresistance have not been identified, but may be due to inhibition of apoptosis. Annexin-A1 has been shown to enhance apoptosis, whilst annexin-A2, by contrast, inhibits apoptosis.


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        • Chuthapisith S.
        • Eremin J.M.
        • El Sheemy M.
        • Eremin O.
        Neoadjuvant chemotherapy in women with large and locally advanced breast cancer: chemoresistance and prediction of response to drug therapy.
        Surgeon. 2006; 4: 211-219
        • Fisher B.
        • Brwon A.
        • Mamounas E.
        • et al.
        Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18.
        J Clin Oncol. 1997; 15: 2483-2493
        • Kaufmann P.
        • Dauphine C.E.
        • Vargas M.P.
        • et al.
        Success of neoadjuvant chemotherapy in conversion of mastectomy to breast conservation surgery.
        Am Surg. 2006; 72: 935-938
        • Jones R.L.
        • Smith I.E.
        Neoadjuvant treatment for early-stage breast cancer: opportunities to assess tumour response.
        Lancet Oncol. 2006; 7: 869-874
        • Chollet P.
        • Amat S.
        • Cure H.
        • et al.
        Prognostic significance of a complete pathological response after induction chemotherapy in operable breast cancer.
        Brit J Cancer. 2002; 86: 1041-1046
        • Smith I.C.
        • Heys S.D.
        • Hutcheon A.W.
        • et al.
        Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel.
        J Clin Oncol. 2002; 20: 1456-1466
        • Chuthapisith S.
        • Layfield R.
        • Kerr I.D.
        • Hughes C.
        • Eremin O.
        Proteomic profiling of MCF-7 breast cancer cells with chemoresistance to different types of anti-cancer drugs.
        Int J Oncol. 2007; 30: 1545-1551
        • Davies R.
        • Budworth J.
        • Riley J.
        • Snowden R.
        • Gescher A.
        • Gant T.W.
        Regulation of P-glycoprotein 1 and 2 gene expression and protein activity in two MCF-7/Dox cell line subclones.
        Brit J Cancer. 1996; 73: 307-315
        • Wosikowski K.
        • Regis J.T.
        • Robery R.W.
        • et al.
        Normal p53 status and function despite the development of drug resistance in human breast cancer cells.
        Cell Growth Differ. 1995; 6: 1395-1403
        • Charafe-Jauffret E.
        • Genestier C.
        • Monville F.
        • et al.
        Gene expression profiling of breast cell lines identifies potential new basal markers.
        Oncogene. 2006; 25: 2273-2284
        • Ross D.T.
        • Scherf U.
        • Eisen M.B.
        • et al.
        Systematic variation in gene expression patterns in human cancer cell lines.
        Nat Genet. 2000; 24: 227-235
        • Lippman M.E.
        • Allergra J.C.
        • Thompson E.B.
        • et al.
        The relation between estrogen receptors and response rate to cytotoxic chemotherapy in metastatic breast cancer.
        New Engl J Med. 1978; 298: 1223-1228
        • Gerke V.
        • Moss S.E.
        Annexins: from structure to function.
        Physiol Rev. 2002; 82: 331-371
        • Sinha P.
        • Hutter G.
        • Kottgen E.
        • Dietel M.
        • Schadendorf D.
        • Lage H.
        Increased expression of annexin I and thioredoxin detected by two-dimensional gel electrophoresis of drug resistant human stomach cancer cells.
        J Biochem Biophys Meth. 1998; 37: 105-116
        • Wang Y.
        • Serfass L.
        • Roy M.O.
        • Wong J.
        • Bonneau A.M.
        • Georges E.
        Annexin-I expression modulates drug resistance in tumor cells.
        Biochem Biophys Res Commun. 2004; 314: 565-570
        • Shen D.
        • Nooraie F.
        • Elshimali Y.
        • et al.
        Decreased expression of annexin A1 is correlated with breast cancer development and progression as determined by a tissue microarray analysis.
        Human Pathol. 2006; 37: 1583-1591
        • Ahn S.H.
        • Sawada H.
        • Ro J.Y.
        • Nicolson G.L.
        Differential expression of annexin I in human mammary ductal epithelial cells in normal and benign and malignant breast tissues.
        Clin Exp Metastasis. 1997; 15: 151-156
        • Alldridge L.C.
        • Bryant C.E.
        Annexin 1 regulates cell proliferation by disruption of cell morphology and inhibition of cyclin D1 expression through sustained activation of the ERK1/2 MAPK signal.
        Exp Cell Res. 2003; 290: 93-107
        • Vishwanatha J.K.
        • Chiang Y.
        • Kumble K.D.
        • Hollingsworth M.A.
        • Pour P.M.
        Enhanced expression of annexin II in human pancreatic carcinoma cells and primary pancreatic cancers.
        Carcinogenesis. 1993; 14: 2575-2579
        • Chen R.
        • Brentnall T.A.
        • Pan S.
        • et al.
        Quantitative proteomics analysis reveals that proteins differentially expressed in chronic pancreatitis are also frequently involved in pancreatic cancer.
        Mol Cell Proteomics. 2007; 6: 1331-1342
        • Zimmermann U.
        • Woenckhaus C.
        • Pietschmann S.
        • et al.
        Expression of annexin II in conventional renal cell carcinoma is correlated with Fuhrman grade and clinical outcome.
        Virchows Arch. 2004; 445: 368-374
        • Sharma M.R.
        • Koltowski L.
        • Ownbey R.T.
        • Tuszynski G.P.
        • Sharma M.C.
        Angiogenesis-associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression.
        Exp Mol Pathol. 2006; 81: 146-156
        • Sharma M.R.
        • Rothman V.
        • Tuszynski G.P.
        • Sharma M.C.
        Antibody-directed targeting of angiostatin’s receptor annexin II inhibits Lewis lung carcinoma tumor growth via blocking of plasminogen activation: possible biochemical mechanism of angiostatin’s action.
        Exp Mol Pathol. 2006; 81: 136-145
        • McColl B.K.
        • Baldwin M.E.
        • Roufail S.
        • et al.
        Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D.
        J Exp Med. 2003; 198: 863-868
        • Huang Y.
        • Yin Y.
        • Yang C.H.
        • et al.
        Involvement of annexin A2 in p53 induced apoptosis in lung cancer.
        Mol Cell Biochem. 2008; 309: 117-123
        • Lim L.H.
        • Pervaiz S.
        Annexin 1: the new face of an old molecule.
        FASEB J. 2007; 21: 968-975
        • Fan X.
        • Krahling S.
        • Smith D.
        • Williamson P.
        • Schlegel R.A.
        Macrophage surface expression of annexins I and II in the phagocytosis of apoptotic lymphocytes.
        Mol Biol Cell. 2004; 15: 2863-2872
        • Erkizan O.
        • Kirkali G.
        • Yorukoglu K.
        • Kirkali Z.
        Significance of heat shock protein-27 expression in patients with renal cell carcinoma.
        Urology. 2004; 64: 474-478
        • Storm F.K.
        • Mahvi D.M.
        • Gilchrist K.W.
        Heat shock protein 27 overexpression in breast cancer lymph node metastasis.
        Ann Surg Oncol. 1996; 3: 570-573
        • Thor A.
        • Benz C.
        • Moore D.
        • et al.
        Stress response protein (srp-27) determination in primary human breast carcinomas: clinical, histologic, and prognostic correlations.
        J Natl Cancer Inst. 1991; 83: 170-178
        • Zhang D.
        • Wong L.L.
        • Koay E.S.
        Phosphorylation of Ser78 of Hsp27 correlated with HER-2/neu status and lymph node positivity in breast cancer.
        Mol Cancer. 2007; 6: 52
        • Laguens G.E.
        • Coronato S.
        • Spinelli O.
        • Laguens R.P.
        • Di Girolamo W.
        Can breast cancer Hsp 27 (Heat Shock Protein 27,000) expression influence axillary lymph node status?.
        Breast. 2001; 10: 179-181
        • Parekh H.K.
        • Deng H.B.
        • Choudhary K.
        • Houser S.R.
        • Simpkins H.
        Overexpression of sorcin, a calcium-binding protein, induces a low level of paclitaxel resistance in human ovarian and breast cancer cells.
        Biochem Pharmacol. 2002; 63: 1149-1158
        • Tan Y.
        • Li G.
        • Zhao C.
        • et al.
        Expression of sorcin predicts poor outcome in acute myeloid leukemia.
        Leukemia Res. 2003; 27: 125-131
        • Jackson J.R.
        • Patrick D.R.
        • Dar M.M.
        • Huang P.S.
        Targeted anti-mitotic therapies: can we improve on tubulin agents?.
        Nat Rev Cancer. 2007; 7: 107-117
        • Alli E.
        • Bash-Babula J.
        • Yang J.M.
        • Hait W.N.
        Effect of stathmin on the sensitivity to antimicrotubule drugs in human breast cancer.
        Cancer Res. 2002; 62: 6864-6869
        • Golouh R.
        • Cufer T.
        • Sadikov A.
        • et al.
        The prognostic value of stathmin-1, S100A2, and SYK proteins in ER-positive primary breast cancer patients treated with adjuvant tamoxifen monotherapy: an immunohistochemical study.
        Breast Cancer Res Treat. 2007; 110: 317-326