Skip to main content

Advertisement

SpringerLink
Log in

Low LATS2 mRNA level can predict favorable response to epirubicin plus cyclophosphamide, but not to docetaxel, in breast cancers

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Putative tumor suppressor genes LATS1 and LATS2 are implicated in the regulation of the cell cycle at the G2/M and G1/S phase, respectively. This study investigated possible correlations of intra-tumoral LATS1 and LATS2 mRNA levels with response to epirubicin plus cyclophosphamide (EC) or docetaxel (DOC) treatment.

Methods

mRNA expression levels of LATS1 and LATS2 were determined by means of real-time PCR assay in 56 locally advanced breast cancers and 15 recurrent breast cancers treated with EC (n = 32) or DOC (n = 39).

Results

Among the patients treated with EC, LATS2 mRNA levels of responders (0.72 ± 0.11, mean ± SE) were significantly (P < 0.05) lower than those of non-responders (1.62 ± 0.44), and responders showed a tendency (P = 0.05) towards reduced LATS1 mRNA levels. Patients with low LATS2 mRNA levels (n = 16) showed a significantly (P < 0.05) higher response rate (75%) to EC treatment than those with high LATS2 mRNA levels (n = 16; response rate = 31%). Positive predictive value, negative predictive value, and diagnostic accuracy of LATS2 mRNA levels for prediction of response to EC were 75, 69, and 72%, respectively. On the other hand, neither LATS1 nor LATS2 mRNA levels were associated with response to DOC treatment.

Conclusion

These results suggest the possibility that intra-tumoral LATS2 mRNA levels may be clinically useful for the prediction of response to EC treatment by breast cancer patients. We speculate that disruption of the checkpoint function at the G1/S phase induced by down-regulation of LATS2 plays some part in the favorable response to EC.

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
Fig. 3

Similar content being viewed by others

References

  • Adachi I, Watanabe T, Takashima S, Narabayashi M, Horikoshi N, Aoyama H, Taguchi T (1996) A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer. Br J Cancer 73:210–216

    PubMed  CAS  Google Scholar 

  • Boege F, Andersen A, Jensen S, Zeidler R, Kreipe H (1995) Proliferation-associated nuclear antigen Ki-S1 is identical with topoisomerase II alpha. Delineation of a carboxy-terminal epitope with peptide antibodies. Am J Pathol 146:1302–1308

    PubMed  CAS  Google Scholar 

  • Bottini A, Berruti A, Bersiga A, Brizzi MP, Bruzzi P, Aguggini S, Brunelli A, Bolsi G, Allevi G, Generali D, Betri E, Bertoli G, Alquati P, Dogliotti L (2001) Relationship between tumour shrinkage and reduction in Ki67 expression after primary chemotherapy in human breast cancer. Br J Cancer 85:1106–1112

    Article  PubMed  CAS  Google Scholar 

  • Capranico G, Zunino F, Kohn KW, Pommier Y (1990) Sequence-selective topoisomerse II inhibition by antracycline derivatives in SV40 DNA: relationship with DNA binding affinity and cytotoxicity. Biochemistry 29:562–569

    Article  PubMed  CAS  Google Scholar 

  • Carter SK (1972) Single and combination nonhormonal chemotherapy in breast cancer. Cancer 30:1543–1555

    Article  PubMed  CAS  Google Scholar 

  • Chang J, Powles TJ, Allred DC, Ashley SE, Clark GM, Makris A, Assersohn L, Gregory RK, Osborne CK, Dowsett M (1999) Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. J Clin Oncol 17:3058–3063

    PubMed  CAS  Google Scholar 

  • Chang J, Ormerod M, Powles TJ, Allred DC, Ashley SE, Dowsett M (2000) Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma. Cancer 89:2145–2152

    Article  PubMed  CAS  Google Scholar 

  • Colleoni M, Orvieto E, Nole F, Orlando L, Minchella I, Viale G, Peruzzotti G, Robertson C, Noberasco C, Galimberti V, Sacchini V, Veronesi P, Zurrida S, Orecchia R, Goldhirsch A (1999) Prediction of response to primary chemotherapy for operable breast cancer. Eur J Cancer 35:574–579

    Article  PubMed  CAS  Google Scholar 

  • Cooke IE, Shelling AN, Le Meuth VG, Charnock ML, Ganesan TS (1996) Allele loss on chromosome arm 6q and fine mapping of the region at 6q27 in epithelial ovarian cancer. Genes Chromosomes Cancer 15:223–233

    Article  PubMed  CAS  Google Scholar 

  • Egawa C, Miyoshi Y, Takamura Y, Taguchi T, Tamaki Y, Noguchi S (2001) Decreased expression of BRCA2 mRNA predicts favorable response to docetaxel in breast cancer. Int J Cancer 95:255–259

    Article  PubMed  CAS  Google Scholar 

  • Egawa C, Motomura K, Miyoshi Y, Takamura Y, Taguchi T, Tamaki Y, Inaji H, Koyama H, Noguchi S (2003) Increased expression of BRCA1 mRNA predicts favorable response to anthracycline-containing chemotherapy in breast cancers. Breast Cancer Res Treat 78:45–50

    Article  PubMed  CAS  Google Scholar 

  • Faneyte IF, Kristel PM, van de Vijver MJ (2001) Determining MDR1/P-glycoprotein expression in breast cancer. Int J Cancer 93:114–122

    Article  PubMed  CAS  Google Scholar 

  • French Epirubicin Study Group (1988) A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 6:679–688

    Google Scholar 

  • Fujii H, Zhou W, Gabrielson E (1996) Detection of frequent allelic loss of 6q23-q25.2 in microdissected human breast cancer tissues. Genes Chromosomes Cancer 16:35–39

    Article  PubMed  CAS  Google Scholar 

  • Geisler S, Lonning PE, Aas T, Johnsen H, Fluge O, Haugen DF, Lillehaug JR, Akslen LA, Borresen-Dale AL (2001) Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer. Cancer Res 61:2505–2512

    PubMed  CAS  Google Scholar 

  • Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133:1710–1715

    PubMed  CAS  Google Scholar 

  • Hasegawa S, Miyoshi Y, Egawa C, Ishitobi M, Taguchi T, Tamaki Y, Monden M, Noguchi S (2003) Prediction of response to docetaxel by quantitative analysis of class I and III beta-tubulin isotype mRNA expression in human breast cancers. Clin Cancer Res 9:2992–2997

    PubMed  CAS  Google Scholar 

  • Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E III, Schilsky RL, Wood WC, Muss HB, Norton L (2003) Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983

    Article  PubMed  CAS  Google Scholar 

  • Hennequin C, Giocanti N, Favaudon V (1995) S-phase specificity of cell killing by docetaxel (Taxotere) in synchronised HeLa cells. Br J Cancer 71:1194–1198

    PubMed  CAS  Google Scholar 

  • Hill BT, Whelan RD (1982) A comparison of the lethal and kinetic effects of doxorubicin and 4’-epi-doxorubicin in vitro. Tumori 68:29–37

    PubMed  CAS  Google Scholar 

  • Hori T, Takaori-Kondo A, Kamikubo Y, Uchiyama T (2000) Molecular cloning of a novel human protein kinase, kpm, that is homologous to warts/lats, a Drosophila tumor suppressor. Oncogene 19:3101–3109

    Article  PubMed  CAS  Google Scholar 

  • Italian Multicentre Breast Study with Epirubicin (1988) Phase III randomised study of fluorouracil, epirubicin and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide, in advanced breast cancer: an Italian multicentre trial. J Clin Oncol 6:976–982

    Google Scholar 

  • Ke H, Pei J, Ni Z, Xia H, Qi H, Woods T, Kelekar A, Tao W (2004) Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-x(L). Exp Cell Res 298:329–338

    Article  PubMed  CAS  Google Scholar 

  • Kulartz M, Knippers R (2004) The replicative regulator protein geminin on chromatin in the HeLa cell cycle. J Biol Chem 279:41686–41694

    Article  PubMed  CAS  Google Scholar 

  • Lee EY, To H, Shew JY, Bookstein R, Scully P, Lee WH (1988) Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science 241:218–221

    Article  PubMed  CAS  Google Scholar 

  • Lee JH, Kavanagh JJ, Wildrick DM, Wharton JT, Blick M (1990) Frequent loss of heterozygosity on chromosomes 6q, 11, and 17 in human ovarian carcinomas. Cancer Res 50:2724–2728

    PubMed  CAS  Google Scholar 

  • Li Y, Pei J, Xia H, Ke H, Wang H, Tao W (2003) Lats2, a putative tumor suppressor, inhibits G1/S transition. Onocogene 22:4398–4405

    Article  CAS  Google Scholar 

  • Linn SC, Pinedo HM, van Ark-Otte J, van der Valk P, Hoekman K, Honkoop AH, Vermorken JB, Giaccone G (1997) Expression of drug resistance proteins in breast cancer, in relation to chemotherapy. Int J Cancer 71:787–795

    Article  PubMed  CAS  Google Scholar 

  • Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N (2005) Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 23:3686–3696

    Article  PubMed  CAS  Google Scholar 

  • Mazurenko N, Attaleb M, Gritsko T, Semjonova L, Pavlova L, Sakharova O, Kisseljov F (1999) High resolution mapping of chromosome 6 deletions in cervical cancer. Oncol Rep 6:859–863

    PubMed  CAS  Google Scholar 

  • Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214

    Article  PubMed  CAS  Google Scholar 

  • Miyoshi Y, Ando A, Takamura Y, Taguchi T, Tamaki Y, Noguchi S (2002) Prediction of response to docetaxel by CYP3A4 mRNA expression in breast cancer tissues. Int J Cancer 97:129–132

    Article  PubMed  CAS  Google Scholar 

  • Noviello C, Courjal F, Theillet C (1996) Loss of heterozygosity on the long arm of chromosome 6 in breast cancer: possibly four regions of deletion. Clin Cancer Res 2:1601–1606

    PubMed  CAS  Google Scholar 

  • Ormrod D, Holm K, Goa K, Spencer C (1999) Epirubicin: a review of its efficacy as adjuvant therapy and in the treatment of metastatic disease in breast cancer. Drugs Aging 15:389–416

    Article  PubMed  CAS  Google Scholar 

  • Pohl G, Rudas M, Taucher S, Stranzl T, Steger GG, Jakesz R, Pirker R, Filipits M (2003) Expression of cell cycle regulatory proteins in breast carcinomas before and after preoperative chemotherapy. Breast Cancer Res Treat 78:97–103

    Article  PubMed  CAS  Google Scholar 

  • Sato T, Saito H, Morita R, Koi S, Lee JH, Nakamura Y (1991) Allelotype of human ovarian cancer. Cancer Res 51:5118–5122

    PubMed  CAS  Google Scholar 

  • Seidman AD, Hudis C, Crown JPA (1993) Phase II evaluation of Taxotere (RP56976 NSC 628503) as initial chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 12:63

    Google Scholar 

  • St John MA, Tao W, Fei X, Fukumoto R, Carcangiu ML, Brownstein DG, Parlow AF, McGrath J, Xu T (1999) Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumors and pituitary dysfunction. Nat Genet 21:182–186

    Article  PubMed  CAS  Google Scholar 

  • Taguchi T, Kato Y, Baba Y, Nishimura G, Tanigaki Y, Horiuchi C, Mochimatsu I, Tsukuda M (2004) Protein levels of p21, p27, cyclin E and Bax predict sensitivity to cisplatin and paclitaxel in head and neck squamous cell carcinomas. Oncol Rep 11:421–426

    PubMed  CAS  Google Scholar 

  • Takahashi Y, Miyoshi Y, Takahata C, Irahara N, Taguchi T, Tamaki Y, Noguchi S (2005) Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin Cancer Res 11:1380–1385

    Article  PubMed  CAS  Google Scholar 

  • Takamura Y, Kobayashi H, Taguchi T, Motomura K, Inaji H, Noguchi S (2002) Prediction of chemotherapeutic response by collagen gel droplet embedded culture-drug sensitivity test in human breast cancers. Int J Cancer 98:450–455

    Article  PubMed  CAS  Google Scholar 

  • Tao W, Zhang S, Turenchalk GS, Stewart RA, St John MA, Chen W, Xu T (1999) Human homologue of the Drosophila melanogaster lats tumor suppressor modulates CDC2 activity. Nat Genet 21:177–181

    Article  PubMed  CAS  Google Scholar 

  • Theile M, Seitz S, Arnold W, Jandrig B, Frege R, Schlag PM, Haensch W, Guski H, Winzer KJ, Barrett JC, Scherneck S (1996) A defined chromosome 6q fragment (at D6S310) harbors a putative tumor suppressor gene for breast cancer. Oncogene 13:677–685

    PubMed  CAS  Google Scholar 

  • Wang H, Roger C (1988) Deletions in human chromosome arms 11p and 13q in primary hepatocellular carcinomas. Cytogenet Cell Genet 48:72–78

    PubMed  CAS  Google Scholar 

  • Xia H, Qi H, Li Y, Pei J, Barton J, Blackstad M, Xu T, Tao W (2002) LATS1 tumor suppressor regulates G2/M transition and apoptosis. Oncogene 21:1233–1241

    Article  PubMed  CAS  Google Scholar 

  • Yabuta N, Fujii T, Copeland NG, Gilbert DJ, Jenkins NA, Nishiguchi H, Endo Y, Toji S, Tanaka H, Nishimune Y, Nojima H (2000) Structure, expression, and chromosome mapping of LATS2, a mammalian homologue of the Drosophila tumor suppressor gene lats/warts. Genomics 63:263–270

    Article  PubMed  CAS  Google Scholar 

  • Yang X, Li D, Chen W, Xu T (2001) Human homologue of the Drosophila lats, LATS1, negatively regulate growth by inducing G2/M arrest or apoptosis. Oncogene 20:6516–6523

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research Priority Area (C) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Author information

Authors and Affiliations

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

    Yuri Takahashi, Yasuo Miyoshi, Koji Morimoto, Tetsuya Taguchi, Yasuhiro Tamaki & Shinzaburo Noguchi

Authors
  1. Yuri Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasuo Miyoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koji Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tetsuya Taguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yasuhiro Tamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shinzaburo Noguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shinzaburo Noguchi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takahashi, Y., Miyoshi, Y., Morimoto, K. et al. Low LATS2 mRNA level can predict favorable response to epirubicin plus cyclophosphamide, but not to docetaxel, in breast cancers. J Cancer Res Clin Oncol 133, 501–509 (2007). https://doi.org/10.1007/s00432-007-0194-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-007-0194-0

Keywords

Search

Navigation