Targeting the MUC1-C Oncoprotein Downregulates HER2 Activation and Abrogates Trastuzumab Resistance in Breast Cancer Cells

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2013 Aug 6

PMID 23912457

Citations 57

Authors

D Raina

Y Uchida

A Kharbanda

H Rajabi

G Panchamoorthy

C Jin

S Kharbanda

M Scaltriti

J Baselga

D Kufe

Affiliations

Soon will be listed here.

Abstract

Patients with HER2-positive breast cancer often exhibit intrinsic or acquired resistance to trastuzumab treatment. The transmembrane mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in breast cancer cells and associates with HER2. The present studies demonstrate that silencing MUC1 C-terminal subunit (MUC1-C) in HER2-overexpressing SKBR3 and BT474 breast cancer cells results in the downregulation of constitutive HER2 activation. Moreover, treatment with the MUC1-C inhibitor, GO-203, was associated with disruption of MUC1-C/HER2 complexes and decreases in tyrosine-phosphorylated HER2 (p-HER2) levels. In studies of trastuzumab-resistant SKBR3R and BT474R cells, we found that the association between MUC1-C and HER2 is markedly increased (∼20-fold) as compared with that in sensitive cells. In addition, silencing MUC1-C in the trastuzumab-resistant cells or treatment with GO-203 decreased p-HER2 and AKT activation. Moreover, targeting MUC1-C was associated with the downregulation of phospho-p27 and cyclin E, which confer trastuzumab resistance. Consistent with these results, targeting MUC1-C inhibited the growth and clonogenic survival of both trastuzumab-resistant cells. Our results further demonstrate that silencing MUC1-C reverses resistance to trastuzumab and that the combination of GO-203 and trastuzumab is highly synergistic. These findings indicate that MUC1-C contributes to constitutive activation of the HER2 pathway and that targeting MUC1-C represents a potential approach to abrogate trastuzumab resistance.

Citing Articles

Cellular polarity pilots breast cancer progression and immunosuppression.

Huang J, Luo S, Shen J, Lee M, Chen R, Ma S Oncogene. 2025; .

PMID: 40057606 DOI: 10.1038/s41388-025-03324-0.

Cardamonin anticancer effects through the modulation of the tumor immune microenvironment in triple-negative breast cancer cells.

Mendonca P, Kaur S, Kirpal B, Soliman K Am J Cancer Res. 2025; 14(12):5644-5664.

PMID: 39803666 PMC: 11711538. DOI: 10.62347/ANXS3815.

Graph-Based Spatial Proximity of Super-Resolved Protein-Protein Interactions Predicts Cancer Drug Responses in Single Cells.

Zhang N, Cai S, Wang M, Hu T, Schneider F, Sun S Cell Mol Bioeng. 2024; 17(5):467-490.

PMID: 39513000 PMC: 11538221. DOI: 10.1007/s12195-024-00822-1.

Preventative Cancer Vaccine-Elicited Human Anti-MUC1 Antibodies Have Multiple Effector Functions.

McKeague M, Lohmueller J, Dracz M, Saadallah N, Ricci E, Beckwith D Antibodies (Basel). 2024; 13(4.

PMID: 39449327 PMC: 11503386. DOI: 10.3390/antib13040085.

Depicting Biomarkers for HER2-Inhibitor Resistance: Implication for Therapy in HER2-Positive Breast Cancer.

Cai A, Chen Y, Wang L, Cusick J, Shi Y Cancers (Basel). 2024; 16(15).

PMID: 39123362 PMC: 11311605. DOI: 10.3390/cancers16152635.

References

Hynes N, Lane H . ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005; 5(5):341-54. DOI: 10.1038/nrc1609. View

Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J . Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007; 99(8):628-38. DOI: 10.1093/jnci/djk134. View

Motti M, De Marco C, Califano D, Fusco A, Viglietto G . Akt-dependent T198 phosphorylation of cyclin-dependent kinase inhibitor p27kip1 in breast cancer. Cell Cycle. 2004; 3(8):1074-80. View

Kufe D . MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncogene. 2012; 32(9):1073-81. PMC: 3621754. DOI: 10.1038/onc.2012.158. View

Chou T, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22:27-55. DOI: 10.1016/0065-2571(84)90007-4. View

Raina D, Ahmad R, Joshi M, Yin L, Wu Z, Kawano T . Direct targeting of the mucin 1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells. Cancer Res. 2009; 69(12):5133-41. PMC: 2721222. DOI: 10.1158/0008-5472.CAN-09-0854. View

Spector N, Blackwell K . Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2009; 27(34):5838-47. DOI: 10.1200/JCO.2009.22.1507. View

Romond E, Perez E, Bryant J, Suman V, Geyer Jr C, Davidson N . Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005; 353(16):1673-84. DOI: 10.1056/NEJMoa052122. View

Guertin A, Martin M, Roberts B, Hurd M, Qu X, Miselis N . Unique functions of CHK1 and WEE1 underlie synergistic anti-tumor activity upon pharmacologic inhibition. Cancer Cell Int. 2012; 12(1):45. PMC: 3517755. DOI: 10.1186/1475-2867-12-45. View

10.

Vermeer P, Einwalter L, Moninger T, Rokhlina T, Kern J, Zabner J . Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature. 2003; 422(6929):322-6. DOI: 10.1038/nature01440. View

11.

Li Y, Yu W, Ren J, Chen W, Huang L, Kharbanda S . Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein. Mol Cancer Res. 2003; 1(10):765-75. View

12.

Kufe D . Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer. 2009; 9(12):874-85. PMC: 2951677. DOI: 10.1038/nrc2761. View

13.

Nahta R, Yuan L, Zhang B, Kobayashi R, Esteva F . Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005; 65(23):11118-28. DOI: 10.1158/0008-5472.CAN-04-3841. View

14.

Scaltriti M, Verma C, Guzman M, Jimenez J, Parra J, Pedersen K . Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2008; 28(6):803-14. DOI: 10.1038/onc.2008.432. View

15.

Scaltriti M, Serra V, Normant E, Guzman M, Rodriguez O, Lim A . Antitumor activity of the Hsp90 inhibitor IPI-504 in HER2-positive trastuzumab-resistant breast cancer. Mol Cancer Ther. 2011; 10(5):817-24. DOI: 10.1158/1535-7163.MCT-10-0966. View

16.

Konecny G, Pegram M, Venkatesan N, Finn R, Yang G, Rahmeh M . Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006; 66(3):1630-9. DOI: 10.1158/0008-5472.CAN-05-1182. View

17.

Slamon D, Clark G, Wong S, Levin W, Ullrich A, McGuire W . Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235(4785):177-82. DOI: 10.1126/science.3798106. View

18.

Scaltriti M, Eichhorn P, Cortes J, Prudkin L, Aura C, Jimenez J . Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc Natl Acad Sci U S A. 2011; 108(9):3761-6. PMC: 3048107. DOI: 10.1073/pnas.1014835108. View

19.

Nahta R, Takahashi T, Ueno N, Hung M, Esteva F . P27(kip1) down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res. 2004; 64(11):3981-6. DOI: 10.1158/0008-5472.CAN-03-3900. View

20.

Wood E, Truesdale A, McDonald O, Yuan D, Hassell A, Dickerson S . A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004; 64(18):6652-9. DOI: 10.1158/0008-5472.CAN-04-1168. View