Gene expression alterations associated with outcome in aromatase inhibitor-treated ER+ early-stage breast cancer patients

TY - JOUR

T1 - Gene expression alterations associated with outcome in aromatase inhibitor-treated ER+ early-stage breast cancer patients

AU - Thomsen, Karina G

AU - Lyng, Maria B

AU - Elias, Daniel

AU - Vever, Henriette

AU - Knoop, Ann S

AU - Lykkesfeldt, Anne E

AU - Lænkholm, Anne-Vibeke

AU - Ditzel, Henrik J

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Aromatase inhibitors (AI), either alone or together with chemotherapy, have become the standard adjuvant treatment for postmenopausal, estrogen receptor-positive (ER+) breast cancer. Although AIs improve overall survival, resistance is still a major clinical problem, thus additional biomarkers predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow-up 6.7 years). Gene expression alterations were validated by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change ≥1.5, p < 0.05), and the gene expression alterations were confirmed using qRT-PCR. Ten of these 26 genes could be linked in a network associated with cellular proliferation, growth, and development. TFF3, which encodes for trefoil factor 3 and is an estrogen-responsive oncogene shown to play a functional role in tamoxifen resistance and metastasis of ER+ breast cancer, was also shown to be upregulated in an AI-resistant cell line model, and reduction of TFF3 levels using TFF3-specific siRNAs decreased the growth of both the AI-resistant and -sensitive parental cell lines. Moreover, overexpression of TFF3 in parental AI-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to the AI exemestane, whereas TFF3 overexpression had no effect on growth in the absence of exemestane, indicating that TFF3 mediates growth and survival signals that abrogate the growth inhibitory effect of exemestane. We identified a panel of 26 genes exhibiting altered expression associated with disease recurrence in patients treated with adjuvant AI monotherapy, including TFF3, which was shown to exhibit a growth- and survival-promoting effect in the context of AI treatment.

AB - Aromatase inhibitors (AI), either alone or together with chemotherapy, have become the standard adjuvant treatment for postmenopausal, estrogen receptor-positive (ER+) breast cancer. Although AIs improve overall survival, resistance is still a major clinical problem, thus additional biomarkers predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow-up 6.7 years). Gene expression alterations were validated by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change ≥1.5, p < 0.05), and the gene expression alterations were confirmed using qRT-PCR. Ten of these 26 genes could be linked in a network associated with cellular proliferation, growth, and development. TFF3, which encodes for trefoil factor 3 and is an estrogen-responsive oncogene shown to play a functional role in tamoxifen resistance and metastasis of ER+ breast cancer, was also shown to be upregulated in an AI-resistant cell line model, and reduction of TFF3 levels using TFF3-specific siRNAs decreased the growth of both the AI-resistant and -sensitive parental cell lines. Moreover, overexpression of TFF3 in parental AI-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to the AI exemestane, whereas TFF3 overexpression had no effect on growth in the absence of exemestane, indicating that TFF3 mediates growth and survival signals that abrogate the growth inhibitory effect of exemestane. We identified a panel of 26 genes exhibiting altered expression associated with disease recurrence in patients treated with adjuvant AI monotherapy, including TFF3, which was shown to exhibit a growth- and survival-promoting effect in the context of AI treatment.

KW - Aged

KW - Androstadienes

KW - Antineoplastic Agents

KW - Aromatase Inhibitors

KW - Breast Neoplasms

KW - Cell Line, Tumor

KW - Chemotherapy, Adjuvant

KW - Drug Resistance, Neoplasm

KW - Eye Proteins

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Middle Aged

KW - Neoplasm Recurrence, Local

KW - Nitriles

KW - Peptides

KW - RGS Proteins

KW - Receptors, Estrogen

KW - Retrospective Studies

KW - Transcription Factors

KW - Treatment Outcome

KW - Trefoil Factor-3

KW - Triazoles

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1007/s10549-015-3644-4

DO - 10.1007/s10549-015-3644-4

M3 - Journal article

C2 - 26585578

SN - 0167-6806

VL - 154

SP - 483

EP - 494

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

IS - 3

ER -