Dose-dependent growth inhibition in response to 72h exposure to the JNK inhibitor SP600125 (a) or the STAT5 Inhibitor II IQDMA (b) on SKBR3 and T47D human breast cancer cells.

<p>Means ± SD.</p

Effect of canertinib (white bar), lapatinib (light grey bar) and afatinib (dark grey bar) on activation (phosphorylation) of ERK/MAPK1/2, STAT3, CREB, STAT5A/B, p70 S6 kinase, IkBa, JNK, and p38 in SKBR3, T47D and Jurkat cells.

<p>Serum-depleted cells were exposed for 6 h to vehicle (0.1% DMSO) or to 1 μM of the TKIs followed by a 3-min challenge with 100 ng/ml EGF and 1 nM HRGb1 and subjected to Milliplex assays. Results are shown relative to vehicle control (100%). Means ± SD.</p

Dose-dependent growth inhibition in response to 72h exposure to lapatinib (a), canertinib (b), or afatinib (c) on malignant human cell lines with no HER2 expression (Jurkat), with moderate HER2 expression (T47D) and with HER2 overexpression (SKBR3).

<p>Means ± SD, n = 3.</p

Characteristics of 114 patients with primary metastatic breast cancer.

<p>HR = hormonal receptor (estrogen and/or progesterone receptor), GGT = gamma-glutamyltransferase, HER2 = human epidermal growth factor 2-receptor</p><p>Characteristics of 114 patients with primary metastatic breast cancer.</p

Schematic representation of HER-dependent signal transduction pathways associated with cell proliferation and apoptosis.

<p>Schematic representation of HER-dependent signal transduction pathways associated with cell proliferation and apoptosis.</p

Effect of the HER-TKI canertinib on the expression of apoptosis-related PARP-1 cleavage products as demonstrated by Western blot analysis of T47D cells grown for 48h (lanes 1–3) and 72h (lanes 4–6) in the absence (lanes 1 and 4), or in the presence of 1μM (lanes 2 and 5) and 10 μM (lanes 3 and 6) canertinib.

<p>Actin was probed on a separate membrane to roughly estimate protein loading.</p

Univariate and multivariable overall-survival analyses.

<p>^aKaplan—Meier analysis (log-rank test)</p><p>^<b>b</b>Multivariable Cox-regression analysis</p><p>*mean (SD) age: 61.0 (13.4) years; GGT = gamma-glutamyltransferase, HER2 = human epidermal growth factor 2-receptor, OS = overall survival, HR = hazard ratio, 95% CI = 95% Confidence Interval</p><p>Univariate and multivariable overall-survival analyses.</p

Dose-dependent effect of SP600125 when given for 72h (a) and time-dependent effect of 5μM canertinib after 2 and 6 hours (b) on apoptosis as examined by Milliplex immunoassay for detection of active (cleaved) caspase 3 in SKBR3 and T47D cells.

<p>Results are shown relative to vehicle (0.1% DMSO) control. Means ± SD.</p

Kaplan-Meier curves for pre-therapeutic GGT levels groups A and B (n = 73, upper line) vs. C and D (n = 41, lower line) and overall survival (<i>P-value</i> for log-rank test <0.041).

<p>Kaplan-Meier curves for pre-therapeutic GGT levels groups A and B (n = 73, upper line) vs. C and D (n = 41, lower line) and overall survival (<i>P-value</i> for log-rank test <0.041).</p

Pre-therapeutic GGT serum levels of patients with primary metastatic breast cancer broken down by clinical-pathological parameters.

<p>* One-way ANOVA</p><p>⁺ Student’s T-test</p><p>^⇞ Values are given as mean (standard deviation), GGT = gamma-glutamyltransferase, HER2 = human epidermal growth factor 2-receptor, SD = standard deviation</p><p>Pre-therapeutic GGT serum levels of patients with primary metastatic breast cancer broken down by clinical-pathological parameters.</p