Breast cancer cells can switch between estrogen receptor alpha and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance
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Breast cancer cells can switch between estrogen receptor alpha and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance. / Sonne-Hansen, Katrine; Norrie, Ida C; Emdal, Kristina Bennet; Benjaminsen, Rikke Vicki; Frogne, Thomas; Christiansen, Ib J; Kirkegaard, Tove; Lykkesfeldt, Anne E.
In: Breast Cancer Research and Treatment, Vol. 121, No. 3, 2010, p. 601-13.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Breast cancer cells can switch between estrogen receptor alpha and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance
AU - Sonne-Hansen, Katrine
AU - Norrie, Ida C
AU - Emdal, Kristina Bennet
AU - Benjaminsen, Rikke Vicki
AU - Frogne, Thomas
AU - Christiansen, Ib J
AU - Kirkegaard, Tove
AU - Lykkesfeldt, Anne E
PY - 2010
Y1 - 2010
N2 - The majority of breast cancers are estrogen responsive, but upon progression of disease other growth promoting pathways are activated, e.g., the ErbB receptor system. The present study focuses on resistance to the pure estrogen antagonist fulvestrant and strategies to treat resistant cells or even circumvent development of resistance. Limited effects were observed when targeting EGFR and ErbB2 with the monoclonal antibodies cetuximab, trastuzumab, and pertuzumab, whereas the pan-ErbB inhibitor CI-1033 selectively inhibited growth of fulvestrant resistant cell lines. CI-1033 inhibited Erk but not Akt signaling, which as well as Erk is important for antiestrogen resistant cell growth. Accordingly, combination therapy with CI-1033 and the Akt inhibitor SH-6 or the Protein Kinase C inhibitor RO-32-0432 was applied and found superior to single agent treatment. Further, the resistant cell lines were more sensitive to CI-1033 treatment when grown in the presence of fulvestrant, as withdrawal of fulvestrant restored signaling through the estrogen receptor alpha (ERalpha), partly overcoming the growth inhibitory effects of CI-1033. Thus, the resistant cells could switch between ERalpha and ErbB signaling for growth promotion. Although parental MCF-7 cell growth primarily depends on ERalpha signaling, a heregulin-1beta induced switch to ErbB signaling rescued MCF-7 cells from the growth inhibition exerted by fulvestrant-mediated blockade of ERalpha signaling. This interplay between ERalpha and ErbB signaling could be abrogated by combined therapy targeting both receptor systems. Thus, the present study indicates that upon development of antiestrogen resistance, antiestrogen treatment should be continued in combination with signal transduction inhibitors. Further, upfront combination of endocrine therapy with pan-ErbB inhibition may postpone or even prevent development of treatment resistance.
AB - The majority of breast cancers are estrogen responsive, but upon progression of disease other growth promoting pathways are activated, e.g., the ErbB receptor system. The present study focuses on resistance to the pure estrogen antagonist fulvestrant and strategies to treat resistant cells or even circumvent development of resistance. Limited effects were observed when targeting EGFR and ErbB2 with the monoclonal antibodies cetuximab, trastuzumab, and pertuzumab, whereas the pan-ErbB inhibitor CI-1033 selectively inhibited growth of fulvestrant resistant cell lines. CI-1033 inhibited Erk but not Akt signaling, which as well as Erk is important for antiestrogen resistant cell growth. Accordingly, combination therapy with CI-1033 and the Akt inhibitor SH-6 or the Protein Kinase C inhibitor RO-32-0432 was applied and found superior to single agent treatment. Further, the resistant cell lines were more sensitive to CI-1033 treatment when grown in the presence of fulvestrant, as withdrawal of fulvestrant restored signaling through the estrogen receptor alpha (ERalpha), partly overcoming the growth inhibitory effects of CI-1033. Thus, the resistant cells could switch between ERalpha and ErbB signaling for growth promotion. Although parental MCF-7 cell growth primarily depends on ERalpha signaling, a heregulin-1beta induced switch to ErbB signaling rescued MCF-7 cells from the growth inhibition exerted by fulvestrant-mediated blockade of ERalpha signaling. This interplay between ERalpha and ErbB signaling could be abrogated by combined therapy targeting both receptor systems. Thus, the present study indicates that upon development of antiestrogen resistance, antiestrogen treatment should be continued in combination with signal transduction inhibitors. Further, upfront combination of endocrine therapy with pan-ErbB inhibition may postpone or even prevent development of treatment resistance.
KW - Antineoplastic Combined Chemotherapy Protocols
KW - Breast Neoplasms
KW - Cell Line, Tumor
KW - Drug Resistance, Neoplasm
KW - Estradiol
KW - Estrogen Receptor alpha
KW - Female
KW - Humans
KW - Morpholines
KW - Oncogene Proteins v-erbB
KW - Signal Transduction
U2 - 10.1007/s10549-009-0506-y
DO - 10.1007/s10549-009-0506-y
M3 - Journal article
C2 - 19697122
VL - 121
SP - 601
EP - 613
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
SN - 0167-6806
IS - 3
ER -
ID: 41844456