Antiestrogen-resistant human breast cancer cells require activated Protein Kinase B/Akt for growth

Abstract

Development of acquired resistance to antiestrogens is a major clinical problem in endocrine treatment of breast cancer patients. The IGF system plays a profound role in many cancer types, including breast cancer. Thus, overexpression and/or constitutive activation of the IGF-I receptor (IGF-IR) or different components of the IGF-IR signaling pathway have been reported to render breast cancer cells less estrogen dependent and capable of sustaining cell proliferation in the presence of antiestrogens. In this study, growth of the antiestrogen-sensitive human breast cancer cell line MCF-7 was inhibited by treatment with IGF-IR-neutralizing antibodies. In contrast, IGF-IR-neutralizing antibodies had no effect on growth of two different antiestrogen-resistant MCF-7 sublines. A panel of antiestrogen-resistant cell lines was investigated for expression of IGF-IR and either undetectable or severely reduced IGF-IR levels were observed. No increase in insulin receptor substrate 1 (IRS-1) or total PKB/Akt (Akt) was detected in the resistant cell lines. However, a significant increase in phosphorylated Akt (pAkt) was found in four of six antiestrogen-resistant cell lines. Overexpression of pAkt was associated with increased Akt kinase activity in both a tamoxifenand an ICI 182,780-resistant cell line. Inhibition of Akt phosphorylation by the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin or the Akt inhibitor SH-6 (structurally modified phosphatidyl inositol ether liquid analog PIA 6) resulted in a more pronounced growth inhibitory effect on the antiestrogen-resistant cells compared with the parental cells, suggesting that signaling via Akt is required for antiestrogen-resistant cell growth in at least a subset of our antiestrogen-resistant cell lines. PTEN expression and activity was not decreased in cell lines overexpressing pAkt. Our data demonstrate that Akt is a target for treatment of antiestrogen-resistant breast cancer cell lines and we suggest that antiestrogen-resistant breast cancer patients may benefit from treatment targeted to inhibit Akt signaling.

Breast cancer cells can switch between estrogen receptor α and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance

“…2 lM CI-1033 inhibited growth of MCF-7 cells to the same extent as the resistant cell lines, indicating general toxicity of the compound at this concentration. Both the PI3-K/Akt and the MEK/Erk pathway are commonly accepted to be downstream of ErbB signaling [32] and we have previously shown upregulation of phosphorylated Akt (pAkt) and Erk (pErk) kinases in a panel of our resistant cell lines [8,11]. In the present study, a marked upregulation of pErk was found in the 164 R -5, 164 R -7, and 182 R -6 cell lines and a modest upregulation of pAkt was observed in the 164 R -5 and 164 R -7 cell lines, Fig 3a. The expression of pErk in the resistant cell lines was quantified by expressing the ratio pErk/Erk in percent of the ratio for MCF-7 cells.…”

“…Several preclinical studies of fulvestrant resistance have reported changes in the ErbB system, consisting of the EGF receptor (EGFR/ HER1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4) receptors and at least 12 activating ligands. The changes correlated with fulvestrant resistance have been observed at the ErbB receptor level, the ligand level, and in ErbB downstream signaling molecules [5][6][7][8][9][10][11]. Consequently, therapies targeting the ErbB system represent an attractive strategy in breast cancer treatment.…”

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

“…Activated Akt can affect the expression and regulation of the responses of hormone receptors and hence leads to ineffectiveness of hormone ablation therapies. [288][289][290][291] Activated Akt has been reported to be present in over 50% of primary AML samples and detection of activated Akt is associated with a poor prognosis. 231 Furthermore, the Akt pathway has been shown to be involved in regulation of multidrug resistance protein-1 and drug resistance in AML and ALL.…”

ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2

“…www.endocrinology-journals.org Previous in vitro and clinical studies have implicated elevated AKT activity in tamoxifen resistance (Jordan et al 2004, Frogne et al 2005, Kirkegaard et al 2005. However, the mechanisms and functional consequences remain somewhat elusive.…”