Parallel Evolution under Chemotherapy Pressure in 29 Breast Cancer Cell Lines Results in Dissimilar Mechanisms of Resistance

Background Developing chemotherapy resistant cell lines can help to identify markers of resistance. Instead of using a panel of highly heterogeneous cell lines, we assumed that truly robust and convergent pattern of resistance can be identified in multiple parallel engineered derivatives of only a few parental cell lines. Methods Parallel cell populations were initiated for two breast cancer cell lines (MDA-MB-231 and MCF-7) and these were treated independently for 18 months with doxorubicin or paclitaxel. IC50 values against 4 chemotherapy agents were determined to measure cross-resistance. Chromosomal instability and karyotypic changes were determined by cytogenetics. TaqMan RT-PCR measurements were performed for resistance-candidate genes. Pgp activity was measured by FACS. Results All together 16 doxorubicin- and 13 paclitaxel-treated cell lines were developed showing 2–46 fold and 3–28 fold increase in resistance, respectively. The RT-PCR and FACS analyses confirmed changes in tubulin isofom composition, TOP2A and MVP expression and activity of transport pumps (ABCB1, ABCG2). Cytogenetics showed less chromosomes but more structural aberrations in the resistant cells. Conclusion We surpassed previous studies by parallel developing a massive number of cell lines to investigate chemoresistance. While the heterogeneity caused evolution of multiple resistant clones with different resistance characteristics, the activation of only a few mechanisms were sufficient in one cell line to achieve resistance.

[1]  Yuan Qi,et al.  Multifactorial approach to predicting resistance to anthracyclines. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  Jie Qi,et al.  Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors. , 2011, Cancer research.

[3]  H. Dressman,et al.  Retraction: Genomic signatures to guide the use of chemotherapeutics , 2011, Nature Medicine.

[4]  C. Desmedt,et al.  Implication of tumor microenvironment in the resistance to chemotherapy in breast cancer patients , 2010, Current opinion in oncology.

[5]  M. Gerlinger,et al.  How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine , 2010, British Journal of Cancer.

[6]  M. Buyse,et al.  Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  Z. Szallasi,et al.  Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  Zoltan Szallasi,et al.  Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer , 2010, Nature Medicine.

[9]  B. Györffy,et al.  PSMB7 is associated with anthracycline resistance and is a prognostic biomarker in breast cancer , 2009, British Journal of Cancer.

[10]  K. Polyak,et al.  Tumor heterogeneity: causes and consequences. , 2010, Biochimica et biophysica acta.

[11]  K. Coombes,et al.  Clinical evaluation of chemotherapy response predictors developed from breast cancer cell lines , 2010, Breast Cancer Research and Treatment.

[12]  B. Győrffy,et al.  1305 PSMB7 is associated with anthracycline resistance and is a prognostic biomarker in breast cancer , 2009 .

[13]  David Cameron,et al.  A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer , 2009, Nature Medicine.

[14]  William Pao,et al.  MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib , 2007, Proceedings of the National Academy of Sciences.

[15]  Joon-Oh Park,et al.  MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling , 2007, Science.

[16]  H. Dressman,et al.  Genomic signatures to guide the use of chemotherapeutics , 2006, Nature Medicine.

[17]  L. Ein-Dor,et al.  Thousands of samples are needed to generate a robust gene list for predicting outcome in cancer. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[18]  C. Denkert,et al.  Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations , 2006, International journal of cancer.

[19]  Carissa A. Sanchez,et al.  Genetic clonal diversity predicts progression to esophageal adenocarcinoma , 2006, Nature Genetics.

[20]  Sang Joon Kim,et al.  A Mathematical Theory of Communication , 2006 .

[21]  I. Petersen,et al.  Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival , 2005, Oncogene.

[22]  Roman Rouzier,et al.  Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[23]  B. Győrffy,et al.  [The problem of multiple testing and solutions for genome-wide studies]. , 2005, Orvosi hetilap.

[24]  E. Martinelli,et al.  Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[25]  Steven J Skates,et al.  Expression of multidrug resistance-1 protein inversely correlates with paclitaxel response and survival in ovarian cancer patients: a study in serial samples. , 2004, Gynecologic oncology.

[26]  T. Hsieh,et al.  ATP-bound Topoisomerase II as a Target for Antitumor Drugs* , 2001, The Journal of Biological Chemistry.

[27]  P. Jansen,et al.  The (patho)physiological functions of the MRP family. , 2000, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[28]  M. Kool,et al.  A family of drug transporters: the multidrug resistance-associated proteins. , 2000, Journal of the National Cancer Institute.

[29]  D. Schadendorf,et al.  Modulation of DNA topoisomerase II activity and expression in melanoma cells with acquired drug resistance , 2000, British Journal of Cancer.

[30]  L. Mørkrid,et al.  Diverse effects of P-glycoprotein inhibitory agents on human leukemia cells expressing the multidrug resistance protein (MRP). , 2000, International journal of clinical pharmacology and therapeutics.

[31]  W. Dalton,et al.  Lung resistance-related protein: determining its role in multidrug resistance. , 1999, Journal of the National Cancer Institute.

[32]  R. Rosell,et al.  Paclitaxel resistance in non-small-cell lung cancer associated with beta-tubulin gene mutations. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  H. Kim,et al.  Levels of multidrug resistance (MDR1) P-glycoprotein expression by human breast cancer correlate with in vitro resistance to taxol and doxorubicin. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  M. Kavallaris,et al.  Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. , 1997, The Journal of clinical investigation.

[35]  C E Shannon,et al.  The mathematical theory of communication. 1963. , 1997, M.D. computing : computers in medical practice.

[36]  F. Baas,et al.  Reduced topoisomerase II activity in multidrug-resistant human non-small cell lung cancer cell lines. , 1995, British Journal of Cancer.

[37]  J. Doroshow,et al.  Prevention of doxorubicin-induced killing of MCF-7 human breast cancer cells by oxygen radical scavengers and iron chelating agents. , 1986, Biochemical and biophysical research communications.

[38]  J. Riordan,et al.  Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. , 1983, Science.

[39]  the original work is properly cited. , 2022 .