Skip to main content

Advertisement

Log in

Microelectrode bioimpedance analysis distinguishes basal and claudin-low subtypes of triple negative breast cancer cells

  • Published:
Biomedical Microdevices Aims and scope Submit manuscript

Abstract

Triple negative breast cancer (TNBC) is highly aggressive and has a poor prognosis when compared to other molecular subtypes. In particular, the claudin-low subtype of TNBC exhibits tumor-initiating/cancer stem cell like properties. Here, we seek to find new biomarkers to discriminate different forms of TNBC by characterizing their bioimpedance. A customized bioimpedance sensor with four identical branched microelectrodes with branch widths adjusted to accommodate spreading of individual cells was fabricated on silicon and pyrex/glass substrates. Cell analyses were performed on the silicon devices which showed somewhat improved inter-electrode and intra-device reliability. We performed detailed analysis of the bioimpedance spectra of four TNBC cell lines, comparing the peak magnitude, peak frequency and peak phase angle between claudin-low TNBC subtype represented by MDA-MB-231 and Hs578T with that of two basal cells types, the TNBC MDA-MB-468, and an immortalized non-malignant basal breast cell line, MCF-10A. The claudin-low TNBC cell lines showed significantly higher peak frequencies and peak phase angles than the properties might be useful in distinguishing the clinically significant claudin-low subtype of TNBC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • M. Abdolahad, M. Janmaleki, M. Taghinejad, H. Taghnejad, F. Salehi, S. Mohajerzadeh, Single-cell resolution diagnosis of cancer cells by carbon nanotube electrical spectroscopy. Nanoscale 5, 3421–3427 (2013)

    Article  Google Scholar 

  • F. Alexander Jr, D.T. Price, S. Bhansali, Optimization of interdigitated electrode (IDE) arrays for impedance based evaluation of Hs 578T cancer cells. Journal of Physics: Conference Series: IOP Publishing, (2010), p. 012134

  • S.K. Arya, K.C. Lee, D. Bin Dah’alan, Daniel, A.R.A. Rahman, Breast tumor cell detection at single cell resolution using an electrochemical impedance technique. Lab. Chip. 12, 2362–8 (2012)

  • F. Asphahani, M. Thein, O. Veiseh, D. Edmondson, R. Kosai, M. Veiseh et al., Influence of cell adhesion and spreading on impedance characteristics of cell-based sensors. Biosens. Bioelectron. 23, 1307–1313 (2008)

    Article  Google Scholar 

  • P. Carotenuto, C. Roma, A.M. Rachiglio, G. Botti, A. D’Alessio, N. Normanno, Triple negative breast cancer: from molecular portrait to therapeutic intervention. Crit. Rev. Eukaryot. Gene Expr. 20, 17–34 (2010)

    Article  Google Scholar 

  • N. Chauveau, L. Hamzaoui, P. Rochaix, B. Rigaud, J.J. Voigt, J.P. Morucci, Ex vivo discrimination between normal and pathological tissues in human breast surgical biopsies using bioimpedance spectroscopy. Electr. Bioimpedance Methods Appl. Med. Biotechnol. 873, 42–50 (1999)

    Google Scholar 

  • K.J. Chavez, S.V. Garimella, S. Lipkowitz, Triple negative breast cancer cell lines: one tool in the search for better treatment of triple negative breast cancer. Breast Dis. 32, 35–48 (2011)

    Google Scholar 

  • L. Chin, J.N. Andersen, P.A. Futreal, Cancer genomics: from discovery science to personalized medicine. Nat. Med. 17, 297–303 (2011)

    Article  Google Scholar 

  • Y. Cho, H.S. Kim, A.B... Frazier, Z.G. Chen, D.M. Shin, A. Han, Whole-cell impedance analysis for highly and poorly metastatic cancer cells. J. Microelectromech. Syst. 18, 808–817 (2009)

  • J. Choi, W.H. Jung, J.S. Koo, Clinicopathologic features of molecular subtypes of triple negative breast cancer based on immunohistochemical markers. Histol. Histopathol. 27, 1481–1493 (2012)

    Google Scholar 

  • B. Cornish, M. Chapman, C. Hirst, B. Mirolo, I. Bunce, L. Ward et al., Early diagnosis of lymphedema using multiple frequency bioimpedance. Lymphology 34, 2–11 (2001)

    Google Scholar 

  • C.J. Creighton, X.X. Li, M. Landis, J.M. Dixon, V.M. Neumeister, A. Sjolund et al., Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl. Acad. Sci. U. S. A. 106, 13820–13825 (2009)

    Article  Google Scholar 

  • F. Di Cello, L. Cope, H.L. Li, J. Jeschke, W. Wang, S.B. Baylin et al., Methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer. PLoS ONE 8, 8 (2013)

    Article  Google Scholar 

  • V.C. Fogg, C.J. Liu, B. Margolis, Multiple regions of Crumbs3 are required for tight junction formation in MCF10A cells. J. Cell Sci. 118, 2859–2869 (2005)

    Article  Google Scholar 

  • R. Gerhard, S. Ricardo, A. Albergaria, M. Gomes, A.R. Silva, A.F. Logullo et al., Immunohistochemical features of claudin-low intrinsic subtype in metaplastic breast carcinomas. Breast 21, 354–360 (2012)

    Article  Google Scholar 

  • I. Giaever, C.R. Keese, A morphological biosensor for mammalian-cells. Nature 366, 591–592 (1993)

    Article  Google Scholar 

  • W.D. Gregory, J.J. Marx, C.W. Gregory, W.M. Mikkelson, J.A. Tjoe, J. Shell, The cole relaxation frequency as a parameter to identify cancer in breast tissue. Med. Phys. 39, 4167–4174 (2012)

    Article  Google Scholar 

  • I.R. Gupta, A.K. Ryan, Claudins: unlocking the code to tight junction function during embryogenesis and in disease. Clin. Genet. 77, 314–325 (2010)

    Article  Google Scholar 

  • A. Han, L. Yang, A.B... Frazier, Quantification of the heterogeneity in breast cancer cell lines using whole-cell impedance spectroscopy. Clin. Cancer Res. 13, 139–143 (2007)

  • J.C. Harrell, A. Prat, J.S. Parker, C. Fan, X.P. He, L. Carey et al., Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse. Breast Cancer Res. Treat. 132, 523–535 (2012)

    Article  Google Scholar 

  • J.C. Harrell, A.D. Pfefferle, N. Zalles, A. Prat, C. Fan, A. Khramtsov, et al. Endothelial-like properties of claudin-low breast cancer cells promote tumor vascular permeability and metastasis. Clin. Exp. Metastasis (2013)

  • K. Heileman, J. Daoud, M. Tabrizian, Dielectric spectroscopy as a viable biosensing tool for cell and tissue characterization and analysis. Biosens. Bioelectron. 49, 348–359 (2013)

    Article  Google Scholar 

  • L.M. Heiser, A. Sadanandam, W.L. Kuo, S.C. Benz, T.C. Goldstein, S. Ng et al., Subtype and pathway specific responses to anticancer compounds in breast cancer. Proc. Natl. Acad. Sci. U. S. A. 109, 2724–2729 (2012)

    Article  Google Scholar 

  • B.T. Hennessy, A.M. Gonzalez-Angulo, K. Stemke-Hale, M.Z. Gilcrease, S. Krishnamurthy, J.S. Lee et al., Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 69, 4116–4124 (2009)

    Article  Google Scholar 

  • J.I. Herschkowitz, W. Zhao, M. Zhang, J. Usary, G. Murrow, D. Edwards et al., Comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells. Proc. Natl. Acad. Sci. U. S. A. 109, 2778–2783 (2012)

    Article  Google Scholar 

  • J.L. Hong, K.C. Lan, L.S. Jang, Electrical characteristics analysis of various cancer cells using a microfluidic device based on single-cell impedance measurement. Sensors Actuators B-Chem. 173, 927–934 (2012)

    Article  Google Scholar 

  • X.Q. Huang, D. Nguyen, D.W. Greve, M.M. Domach, Simulation of microelectrode impedance changes due to cell growth. IEEE Sensors J. 4, 576–583 (2004)

    Article  Google Scholar 

  • C.A. Hudis, L. Gianni, Triple-negative breast cancer: an unmet medical need. Oncologist 16, 1–11 (2011)

    Article  Google Scholar 

  • H.-G. Jahnke, A. Heimann, R. Azendorf, K. Mpoukouvalas, O. Kempski, A.A. Robitzki et al., Impedance spectroscopy—an outstanding method for label-free and real-time discrimination between brain and tumor tissue in vivo. Biosens. Bioelectron. 46, 8–14 (2013)

    Article  Google Scholar 

  • C.M. Lo, C.R. Keese, I. Giaever, Impedance analysis of MDCK cells measured by electric cell-substrate impedance sensing. Biophys. J. 69, 2800–2807 (1995)

    Article  Google Scholar 

  • S.L. Lu, K. Singh, S. Mangray, R. Tavares, L. Noble, M.B. Resnick et al., Claudin expression in high-grade invasive ductal carcinoma of the breast: correlation with the molecular subtype. Mod. Pathol. 26, 485–495 (2013)

    Article  Google Scholar 

  • A. Marshall, V. Pai, M. Sartor, N. Horseman, In vitro multipotent differentiation and barrier function of a human mammary epithelium. Cell Tissue Res. 335, 383–395 (2009)

    Article  Google Scholar 

  • H. Masuda, K.A. Baggerly, Y. Wang, Y. Zhang, A.M. Gonzalez-Angulo, F. Meric-Bernstam, et al. Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes. Clin. Cancer Res. (2013)

  • T. Morimoto, S. Kimura, Y. Konishi, K. Komaki, T. Uyama, Y. Monden et al., A study of the electrical bio-impedance of tumors. Investig. Surg. 6, 25–32 (1993)

    Article  Google Scholar 

  • S. Narayanan, M. Nikkhah, J.S. Strobl, M. Agah, Analysis of the passivation layer by testing and modeling a cell impedance micro-sensor. Sensors Actuators A-Phys. 159, 241–247 (2010)

    Article  Google Scholar 

  • R.M. Neve, K. Chin, J. Fridlyand, J. Yeh, F.L. Baehner, T. Fevr et al., A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10, 515–527 (2006)

    Article  Google Scholar 

  • E.Y.K. Ng, S.V. Sree, K.H. Ng, G. Kaw, The use of tissue electrical characteristics for breast cancer detection: a perspective review. Technol. Cancer Res. Treat. 7, 295–308 (2008)

    Article  Google Scholar 

  • H. Pick, S. Terrettaz, O. Baud, O. Laribi, C. Brisken, H. Vogel, Monitoring proliferative activities of hormone-like odorants in human breast cancer cells by gene transcription profiling and electrical impedance spectroscopy. Biosens. Bioelectron. 50, 431–436 (2013)

    Article  Google Scholar 

  • A. Prat, C.M. Perou, Deconstructing the molecular portraits of breast cancer. Mol. Oncol. 5, 5–23 (2011)

    Article  Google Scholar 

  • A. Prat, J.S. Parker, O. Karginova, C. Fan, C. Livasy, J.I. Herschkowitz et al., Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 12, 18 (2010)

    Article  Google Scholar 

  • D.T. Price, A.R.A. Rahman, S. Bhansali, Design rule for optimization of microelectrodes used in electric cell-substrate impedance sensing (ECIS). Biosens. Bioelectron. 24, 2071–2076 (2009)

    Article  Google Scholar 

  • G.F. Qiao, W. Wang, W. Duan, F. Zheng, A.J. Sinclair, C.R. Chatwin, Bioimpedance analysis for the characterization of breast cancer cells in suspension. IEEE Trans. Biomed. Eng. 59, 2321–2329 (2012)

    Article  Google Scholar 

  • E.A. Rakha, S. Chan, Metastatic triple-negative breast cancer. Clin. Oncol. 23, 587–600 (2011)

    Article  Google Scholar 

  • O. Raneta, V. Bella, L. Bellova, E. Zamecnikova, The use of electrical impedance tomography to the differential diagnosis of pathological mammographic/sonographic findings. Neoplasma 60, 647–654 (2013)

    Article  Google Scholar 

  • S. Ricardo, R. Gerhard, J.F. Cameselle-Teijeiro, F. Schmitt, J. Paredes, Claudin expression in breast cancer: high or low, what to expect? Histol. Histopathol. 27, 1283–1295 (2012)

    Google Scholar 

  • A. Romero, A. Prat, J.A. García-Sáenz, N.del Prado, A. Pelayo, V. Furió, et al. Assignment of tumor subtype by genomic testing and pathologic-based approximations: implications on patient’s management and therapy selection. Clin. Transl. Oncol. (2013)

  • D. Sarrió, S. M. Rodriguez-Pinilla, D. Hardisson, A. Cano, G. Moreno-Bueno, J. Palacios, Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 68, 989–997 (2008)

  • D. Sarrio, J. Palacios, M. Hergueta-Redondo, G. Gomez-Lopez, A. Cano, G. Moreno-Bueno, Functional characterization of E- and P-cadherin in invasive breast cancer cells. BMC Cancer 9, 14 (2009)

    Article  Google Scholar 

  • D. Sarrio, C.K. Franklin, A. Mackay, J.S. Reis, C.M. Isacke, Epithelial and mesenchymal subpopulations within normal basal breast cell lines exhibit distinct stem cell/progenitor properties. Stem Cells 30, 292–303 (2012)

    Article  Google Scholar 

  • C.L. Sommers, S.W. Byers, E.W. Thompson, J.A. Torri, E.P. Gelmann, Differentiation state and invasiveness of human breast cancer cell lines. Breast Cancer Res. Treat. 31, 325–335 (1994)

    Article  Google Scholar 

  • V. Srinivasaraghavan, J. Strobl, M. Agah, Chemical Induced Impedance Spectroscopy for Single Cancer Cell Detection (Solid-State Sensors, Actuators and Microsystems Conference (Transducers), Beijing, 2011a), pp. 2247–2250

  • V. Srinivasaraghavan, J. Strobl, M. Agah, Detection of Breast Cancer Cells in Tri-Culture Using Impedance Spectroscopy. 15th International Conference on Miniaturized Systems for Chemistry and Life Sciences (MicroTAS, Seattle, 2011b), pp. 1713–1715

    Google Scholar 

  • V. Srinivasaraghavan, J. Strobl, M. Agah, Bioimpedance rise in response to histone deacetylase inhibitor is a marker of mammary cancer cells within a mixed culture of normal breast cells. Lab Chip 12, 5168–5179 (2012)

    Article  Google Scholar 

  • V. Srinivasaraghavan, J. Strobl, D. Wang, J.R. Heflin, M. Agah, A comparative study of nano-scale coatings on gold electrodes for bioimpedance studies of breast cancer cells. Biomed Microdevices 1–8 (2014)

  • J.S. Strobl, M. Nikkhah, M. Agah, Actions of the anti-cancer drug suberoylanilide hydroxamic acid (SAHA) on human breast cancer cytoarchitecture in silicon microstructures. Biomaterials 31, 7043–7050 (2010)

    Article  Google Scholar 

  • V. Walia, Y. Yu, D. Cao, M. Sun, J.R. McLean, B.G. Hollier et al., Loss of breast epithelial marker hCLCA2 promotes epithelial-to-mesenchymal transition and indicates higher risk of metastasis. Oncogene 31, 2237–2246 (2012)

    Article  Google Scholar 

  • J. Wegener, C.R. Keese, I. Giaever, Electric cell-substrate impedance sensing (ECIS) as a noninvasive means to monitor the kinetics of cell spreading to artificial surfaces. Exp. Cell Res. 259, 158–166 (2000)

    Article  Google Scholar 

  • X.Y. Wu, H.X. Chen, B. Parker, E. Rubin, T. Zhu, J.S. Lee et al., HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial-mesenchymal transition. Cancer Res. 66, 9527–9534 (2006)

    Article  Google Scholar 

  • L.J. Yang, L.R. Arias, T.S. Lane, M.D. Yancey, J. Mamouni, Real-time electrical impedance-based measurement to distinguish oral cancer cells and non-cancer oral epithelial cells. Anal. Bioanal. Chem. 399, 1823–1833 (2011)

    Article  Google Scholar 

  • D.R. Youlden, S.M. Cramb, N.A.M. Dunn, J.M. Muller, C.M. Pyke, P.D. Baade, The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol. 36, 237–248 (2012)

    Article  Google Scholar 

Download references

Acknowledgments

We acknowledge the morphology service laboratory and Kathy Lowe for support with sample preparation for SEM imaging. This work was primarily supported by the National Science Foundation IDR Award: ECCS-0925945.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Masoud Agah.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Srinivasaraghavan, V., Strobl, J. & Agah, M. Microelectrode bioimpedance analysis distinguishes basal and claudin-low subtypes of triple negative breast cancer cells. Biomed Microdevices 17, 80 (2015). https://doi.org/10.1007/s10544-015-9977-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s10544-015-9977-2

Keywords

Navigation