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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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: 177–182.
Hynes NE, Lane HA . ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005; 5: 341–354.
Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF 3rd, Hynes NE . The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA 2003; 100: 8933–8938.
Baselga J, Swain SM . Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer 2009; 9: 463–475.
Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 2009; 15: 429–440.
Klapper LN, Waterman H, Sela M, Yarden Y . Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res 2000; 60: 3384–3388.
Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene 2009; 28: 803–814.
Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med 2002; 8: 1145–1152.
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783–792.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr., Davidson NE et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673–1684.
Spector NL, Blackwell KL . Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2009; 27: 5838–5847.
Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004; 6: 117–127.
Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007; 12: 395–402.
Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW et al. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med 2011; 17: 461–469.
Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J et al. 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: 628–638.
Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ . 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: 11118–11128.
Shattuck DL, Miller JK, Carraway KL III, Sweeney C . Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res 2008; 68: 1471–1477.
Huang X, Gao L, Wang S, McManaman JL, Thor AD, Yang X et al. Heterotrimerization of the growth factor receptors erbB2, erbB3, and insulin-like growth factor-1 receptor in breast cancer cells resistant to herceptin. Cancer Res 2010; 70: 1204–1214.
Mittendorf EA, Wu Y, Scaltriti M, Meric-Bernstam F, Hunt KK, Dawood S et al. Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin Cancer Res 2009; 15: 7381–7388.
Scaltriti M, Eichhorn PJ, Cortes J, Prudkin L, Aura C, Jimenez J et al. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc Natl Acad Sci USA 2011; 108: 3761–3766.
Nahta R, Takahashi T, Ueno NT, Hung MC, Esteva FJ . P27(kip1) down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res 2004; 64: 3981–3986.
Lee-Hoeflich ST, Pham TQ, Dowbenko D, Munroe X, Lee J, Li L et al. PPM1H is a p27 phosphatase implicated in trastuzumab resistance. Cancer Discov 2011; 1: 326–337.
Li Y, Yu W-H, Ren J, Huang L, Kharbanda S, Loda M et al. Heregulin targets γ-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 protein. Mol Cancer Res 2003; 1: 765–775.
Kufe D . MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncogene 2013; 32: 1073–1081.
Kufe D . Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer 2009; 9: 874–885.
Duraisamy S, Kufe T, Ramasamy S, Kufe D . Evolution of the human MUC1 oncoprotein. Int J Oncol 2007; 31: 671–677.
Raina D, Kosugi M, Ahmad R, Panchamoorthy G, Rajabi H, Alam M et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther 2011; 10: 806–816.
Li Y, Liu D, Chen D, Kharbanda S, Kufe D . Human DF3/MUC1 carcinoma-associated protein functions as an oncogene. Oncogene 2003; 22: 6107–6110.
Huang L, Chen D, Liu D, Yin L, Kharbanda S, Kufe D . MUC1 oncoprotein blocks GSK3β-mediated phosphorylation and degradation of β-catenin. Cancer Res 2005; 65: 10413–10422.
Leng Y, Cao C, Ren J, Huang L, Chen D, Ito M et al. Nuclear import of the MUC1-C oncoprotein is mediated by nucleoporin Nup62. J Biol Chem 2007; 282: 19321–19330.
Raina D, Ahmad R, Joshi M, Yin L, Wu Z, Kawano T et al. Direct targeting of the MUC1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells. Cancer Res 2009; 69: 5133–5141.
Raina D, Ahmad R, Rajabi H, Panchamoorthy G, Kharbanda S, Kufe D . Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells. Int J Oncol 2012; 40: 1643–1649.
Scaltriti M, Serra V, Normant E, Guzman M, Rodriguez O, Lim AR et al. Antitumor activity of the Hsp90 inhibitor IPI-504 in HER2-positive trastuzumab-resistant breast cancer. Mol Cancer Ther 2011; 10: 817–824.
Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 2008; 68: 5878–5887.
Viglietto G, Motti ML, Bruni P, Melillo RM, D’Alessio A, Califano D et al. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 2002; 8: 1136–1144.
Motti ML, 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: 1074–1080.
Buck E, Eyzaguirre A, Brown E, Petti F, McCormack S, Haley JD et al. Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther 2006; 5: 2676–2684.
Guertin AD, Martin MM, Roberts B, Hurd M, Qu X, Miselis NR et al. Unique functions of CHK1 and WEE1 underlie synergistic anti-tumor activity upon pharmacologic inhibition. Cancer Cell Int 2012; 12: 45.
Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH et al. 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: 6652–6659.
Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 2006; 66: 1630–1639.
Nahta R, Yuan LX, Du Y, Esteva FJ . Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling. Mol Cancer Ther 2007; 6: 667–674.
Fessler S, Wotkowicz M, Mahanta S, Bamdad C . MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells. Breast Cancer Res Treat 2009; 118: 113–124.
Mittendorf EA, Liu Y, Tucker SL, McKenzie T, Qiao N, Akli S et al. A novel interaction between HER2/neu and cyclin E in breast cancer. Oncogene 2010; 29: 3896–3907.
Li P, Li C, Zhao X, Zhang X, Nicosia SV, Bai W . P27(Kip1) stabilization and G(1) arrest by 1,25-dihydroxyvitamin D(3) in ovarian cancer cells mediated through down-regulation of cyclin E/cyclin-dependent kinase 2 and Skp1-Cullin-F-box protein/Skp2 ubiquitin ligase. J Biol Chem 2004; 279: 25260–25267.
Vermeer PD, Einwalter LA, Moninger TO, Rokhlina T, Kern JA, Zabner J et al. Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature 2003; 422: 322–326.
Chou TC, Talalay P . Quantitative analysis of dose–effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984; 22: 27–55.
Chou TC . Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 2010; 70: 440–446.
Acknowledgements
This work was supported by Grants CA97098 and CA166480 awarded by the National Cancer Institute, and by the Susan G Komen for the Cure Grant SAC110046 (MS and JB).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
DK holds equity in Genus Oncology and is a consultant to the company. The other authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Rights and permissions
About this article
Cite this article
Raina, D., Uchida, Y., Kharbanda, A. et al. Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells. Oncogene 33, 3422–3431 (2014). https://doi.org/10.1038/onc.2013.308
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2013.308
Keywords
This article is cited by
-
Pyrotinib-based therapeutic approaches for HER2-positive breast cancer: the time is now
Breast Cancer Research (2023)
-
Anti-MUC1 nanobody conjugated by chitosan nanoparticle with enhancement of anti-proliferation activity in breast cancer cell lines
Chemical Papers (2023)
-
MUC1 triggers lineage plasticity of Her2 positive mammary tumors
Oncogene (2022)
-
HER2-Positive Breast Cancer Immunotherapy: A Focus on Vaccine Development
Archivum Immunologiae et Therapiae Experimentalis (2020)
-
Caveolin-1 mediates cellular distribution of HER2 and affects trastuzumab binding and therapeutic efficacy
Nature Communications (2018)