TY - JOUR

T1 - Parallel Evolution under Chemotherapy Pressure in 29 Breast Cancer Cell Lines Results in Dissimilar Mechanisms of Resistance

A1 - Tegze,Balint

A1 - Szallasi,Zoltan Imre

A1 - Haltrich,Iren

A1 - Penzvalto,Zsofia

A1 - Toth,Zsuzsa

A1 - Liko,Istvan

A1 - Gyoerffy,Balazs

AU - Tegze,Balint

AU - Szallasi,Zoltan Imre

AU - Haltrich,Iren

AU - Penzvalto,Zsofia

AU - Toth,Zsuzsa

AU - Liko,Istvan

AU - Gyoerffy,Balazs

PB - Public Library of Science

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - BIOLOGY

KW - TOPOISOMERASE-II ACTIVITY

KW - MULTIDRUG-RESISTANCE

KW - LUNG-CANCER

KW - PACLITAXEL RESISTANCE

KW - PREDICTS RESISTANCE

KW - ACQUIRED-RESISTANCE

KW - EXPRESSION

KW - PROTEIN

KW - AMPLIFICATION

KW - DOXORUBICIN

U2 - 10.1371/journal.pone.0030804

DO - 10.1371/journal.pone.0030804

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 2

VL - 7

SP - e30804

ER -