PTEN Activity Could Be a Predictive Marker of Trastuzumab Efficacy in the Treatment of ErbB2-overexpressing Breast Cancer

Overview

Journal Br J Cancer

Specialty Oncology

Date 2006 Jan 13

PMID 16404430

Citations 54

Authors

T Fujita

H Doihara

K Kawasaki

D Takabatake

H Takahashi

K Washio

K Tsukuda

Y Ogasawara

N Shimizu

Affiliations

Soon will be listed here.

Abstract

Trastuzumab is the only HER2/neu-directed therapy to have received Food and Drug Administration approval for the treatment of patients with metastatic breast cancer. The efficacy of trastuzumab depends on the HER2/neu status of the tumour and the patient's prior treatment, but even when patients are selected on the basis of HER2/neu gene amplification, the single-agent response rate ranges from 12 to 30% and few patients respond to trastuzumab monotherapy. Here, we propose PTEN as a predictive biomarker for trastuzumab efficacy. Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were investigated. We also examined clinical samples from patients who had been treated with trastuzumab and analysed the relationship between trastuzumab efficacy and PTEN level. The PI3K/Akt signalling pathway was observed to be highly active in the drug-resistant cells, and their level of PTEN was low. Delivery of antisense PTEN duplex siRNA significantly decreased the trastuzumab chemosensitivity of parental SKBR3 cells, and marked activation of Akt signalling pathway was also recognised. Moreover, immunohistochemical investigation revealed that trastuzumab treatment was remarkably successful in cells with elevated PTEN expression. Along with the immune-system-associated cytotoxic mechanism, several mechanisms have been proposed for the effect of trastuzumab. PTEN activity might play an important and major role in its HER2/PI3K/Akt-mediated antitumour effect, and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of breast cancer.

Citing Articles

HER2-Positive Breast Cancer Treatment and Resistance.

Veeraraghavan J, De Angelis C, Gutierrez C, Liao F, Sabotta C, Rimawi M Adv Exp Med Biol. 2025; 1464():495-525.

PMID: 39821040 DOI: 10.1007/978-3-031-70875-6_24.

The PTEN and ATM axis controls the G1/S cell cycle checkpoint and tumorigenesis in HER2-positive breast cancer.

Bassi C, Fortin J, Snow B, Wakeham A, Ho J, Haight J Cell Death Differ. 2021; 28(11):3036-3051.

PMID: 34059798 PMC: 8564521. DOI: 10.1038/s41418-021-00799-8.

Advanced Approaches to Breast Cancer Classification and Diagnosis.

Zubair M, Wang S, Ali N Front Pharmacol. 2021; 11:632079.

PMID: 33716731 PMC: 7952319. DOI: 10.3389/fphar.2020.632079.

Towards personalized treatment for early stage HER2-positive breast cancer.

Goutsouliak K, Veeraraghavan J, Sethunath V, De Angelis C, Osborne C, Rimawi M Nat Rev Clin Oncol. 2019; 17(4):233-250.

PMID: 31836877 PMC: 8023395. DOI: 10.1038/s41571-019-0299-9.

BioPATH: A Biomarker Study in Asian Patients with HER2+ Advanced Breast Cancer Treated with Lapatinib and Other Anti-HER2 Therapy.

Kim S, Do I, Tsang J, Kim T, Yap Y, Cornelio G Cancer Res Treat. 2019; 51(4):1527-1539.

PMID: 31163957 PMC: 6790855. DOI: 10.4143/crt.2018.598.

References

Garcia J, Silva J, Dominguez G, Gonzalez R, Navarro A, Carretero L . Allelic loss of the PTEN region (10q23) in breast carcinomas of poor pathophenotype. Breast Cancer Res Treat. 2000; 57(3):237-43. DOI: 10.1023/a:1006273516976. View

Lu Y, Lin Y, Lapushin R, Cuevas B, Fang X, Yu S . The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene. 1999; 18(50):7034-45. DOI: 10.1038/sj.onc.1203183. View

Yu D, Hung M . Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene. 2001; 19(53):6115-21. DOI: 10.1038/sj.onc.1203972. View

Torres J, Pulido R . The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J Biol Chem. 2000; 276(2):993-8. DOI: 10.1074/jbc.M009134200. View

Depowski P, Rosenthal S, Ross J . Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol. 2001; 14(7):672-6. DOI: 10.1038/modpathol.3880371. View

Albanell J, Baselga J . Unraveling resistance to trastuzumab (Herceptin): insulin-like growth factor-I receptor, a new suspect. J Natl Cancer Inst. 2001; 93(24):1830-2. DOI: 10.1093/jnci/93.24.1830. View

Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M . Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst. 2001; 93(24):1852-7. DOI: 10.1093/jnci/93.24.1852. View

Lu Y, Zi X, Pollak M . Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells. Int J Cancer. 2003; 108(3):334-41. DOI: 10.1002/ijc.11445. View

Nahta R, Esteva F . In vitro effects of trastuzumab and vinorelbine in trastuzumab-resistant breast cancer cells. Cancer Chemother Pharmacol. 2003; 53(2):186-90. DOI: 10.1007/s00280-003-0728-3. View

10.

Carraway H, Hidalgo M . New targets for therapy in breast cancer: mammalian target of rapamycin (mTOR) antagonists. Breast Cancer Res. 2004; 6(5):219-24. PMC: 549184. DOI: 10.1186/bcr927. View

11.

Crowder R, Lombardi D, Ellis M . Successful targeting of ErbB2 receptors-is PTEN the key?. Cancer Cell. 2004; 6(2):103-4. DOI: 10.1016/j.ccr.2004.08.001. View

12.

Nagata Y, Lan K, Zhou X, Tan M, Esteva F, Sahin A . PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004; 6(2):117-27. DOI: 10.1016/j.ccr.2004.06.022. View

13.

Friedrichs K, Gluba S, Eidtmann H, Jonat W . Overexpression of p53 and prognosis in breast cancer. Cancer. 1993; 72(12):3641-7. DOI: 10.1002/1097-0142(19931215)72:12<3641::aid-cncr2820721215>3.0.co;2-8. View

14.

Louis D, Gusella J . A tiger behind many doors: multiple genetic pathways to malignant glioma. Trends Genet. 1995; 11(10):412-5. DOI: 10.1016/s0168-9525(00)89125-8. View

15.

Chui X, Egami H, Yamashita J, Kurizaki T, Ohmachi H, Yamamoto S . Immunohistochemical expression of the c-kit proto-oncogene product in human malignant and non-malignant breast tissues. Br J Cancer. 1996; 73(10):1233-6. PMC: 2074515. DOI: 10.1038/bjc.1996.236. View

16.

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S . PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997; 275(5308):1943-7. DOI: 10.1126/science.275.5308.1943. View

17.

Tashiro H, Blazes M, Wu R, Cho K, Bose S, Wang S . Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res. 1997; 57(18):3935-40. View

18.

Risinger J, Hayes A, Berchuck A, Barrett J . PTEN/MMAC1 mutations in endometrial cancers. Cancer Res. 1997; 57(21):4736-8. View

19.

Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M, Herman J . Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res. 1997; 57(22):4997-5000. View

20.

Teng D, Hu R, Lin H, Davis T, Iliev D, Frye C . MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res. 1997; 57(23):5221-5. View