Fig 2: Molecular subtyping of BRCA1-defecient mammary tumors. A. 23 BRCA1-defecient mammary tumors are hierarchically clustered into four subgroups based on whole transcriptome. The genotype, intrinsic cancer subtype based on PAM50, ERa/PR/ERBB2 expression patterns based on IHC staining as well as mRNA levels of several selected genes are shown. B. The expression patterns of KRT14, KRT18, E-Cadherin and Vimentin in 4 BRCA1-defecient mammary tumors are shown by immune-fluorescence stained sections. The 4 tumors were from 4 distinct subgroups shown in panel A. Scale bar, 50µm. C. Boxplots representing Z-scale normalized gene expression values from 4 subgroups of BRCA1-defecient mammary tumors show expression levels of different groups of genes (Figure S3). The box represents the interquartile range and the line is the median. D. The sensitivities of 8 Brca1-mutant mouse mammary cell lines to cisplatin (left panel) and olaparib (right panel). The colors of the lines represent the subtypes of the mammary tumors where the cell lines were derived. Wilcox-rank sum test was conducted for the analysis of drug sensitivity between mesenchymal-like tumors and the other 3 groups. ns, no significance; *, P < 0.05; **, P < 0.01, and ***, P < 0.001.

Fig 3: Lapatinib treatment induces higher serum levels of HER2 in patients with castration-resistant prostate cancer. a Waterfall plot demonstrating the change in EGFR levels in the serum of patients enrolled in a previously reported single-arm open-label Phase II trial on lapatinib (n = 13).20 Note that only 3/13(23%) experienced a decrease in serum levels of EGFR. Median % change in EGFR (pre- vs post-treatment) was +3.48% (range: -18.7% to +49.1%), mean increase: 6.66%; however, this increase was not significant (p = 0.3353). b In contrast, only 1/13 = 7.7% experienced any decrease in HER2. Median % change in HER2 (pre- vs post-treatment) was +40.35% (range: -2.02% to + 120.83%); mean increase: 42.6%, p = 0.0022. c Patients were classified according to “low” PSA changes (PSA change less than 2-fold) that of pre-treatment levels following lapatinib treatment at the time of progression, vs “high” PSA changes—(PSA change > 2-fold), providing two non-overlapping groups (p = 0.0012). d Percent changes in EGFR were not significantly different between the “low” and “high” PSA groups (p = 0.1014) e but percent change in HER2 correlated strongly with change in PSA for the duration of the treatment (p = 0.035)

Fig 4: Effects of rNrg1ß pretreatment on the Nrg1 signaling in primary mouse cortical neurons exposed to Aß1–42. The (A) relative levels of the Nrg1 isoforms, (B) phosphorylation levels of Neu and ErbB4, (C) pAkt1 levels and (D) pErk1/2 levels in primary cortical neurons pretreated with rNrg1ß at a concentration of 5 or 10 nM for 2 h prior to a 24-h treatment with 10 µM oligomeric Aß1–42 are shown (n=5, one-way analysis of variance with Tukey's post-hoc test; data are expressed as the mean ± standard error of the mean). Double immunofluorescence staining of ß-III tubulin with either (E) pErbB4 or (F) pNeu in the cortical neurons pretreated with rNrg1ß at a concentration of 5 or 10 nM for 2 h prior to a 24 h treatment with 10 µM oligomeric Aß1–42. Scale bars=20 µm. rNRG1ß, recombinant neuregulin 1ß, pErbB4, phosphorylated ErbB4; pNeu, phosphorylated Neu; pErk1/2, phosphorylated extracellular-regulated signal kinase 1/2; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Aß, amyloid-beta; DAPI, 4',6-diamidino-2-phenylindole. #P<0.05 and ##P<0.01 vs. vehicle control and *P<0.05, **P<0.01 and ***P<0.001 compared with the control group.

Fig 5: Intertumor heterogeneity of BRCA1-defecient mammary tumors. A. Summary of the tumor free time of 23 BRCA1-defecient mouse mammary tumors. The tumors are grouped as their PAM50 subtyping and marked according to their genotype. BrT (red), mammary tumors from MMTV-Cre; Brca1fl/fl mice; Br53T (green), mammary tumors from MMTV-Cre; Brca1fl/fl; Trp53fl/+ mice. B. Distinct histopathological features of BRCA1-defecient mammary tumors are shown by H&E stained sections: (a), one tumor with mesenchymal/fibroblast-like feature; (b), one tumor with glandular structure; (c), one tumor with medullary feature; (d), one tumor with net-like feature and typical pushing margins. C. Distinct expression patterns of ERalpha, PR and ERBB2 in BRCA1-defecient mammary tumors are shown by IHC stained sections. Scale bar, 50 µm.