Activated c-SRC in ductal carcinoma in situ correlates with high tumour grade, high proliferation and HER2 positivity - PubMed (original) (raw)

Activated c-SRC in ductal carcinoma in situ correlates with high tumour grade, high proliferation and HER2 positivity

G R Wilson et al. Br J Cancer. 2006.

Abstract

Overexpression and/or activity of c-Src non-receptor tyrosine kinase is associated with progression of several human epithelial cancers including breast cancer. c-Src activity in 'pure' ductal carcinoma in situ (DCIS) was measured to assess whether this predicts recurrence and/or correlates with HER2 expression and other clinical parameters. Activated c-Src levels were evaluated in DCIS biopsies from 129 women, with median follow-up at 60 months. High levels of activated c-Src correlated with HER2 positivity, high tumour grade, comedo necrosis and elevated epithelial proliferation. In univariate analysis, high activated c-Src level associated with lower recurrence-free survival at 5 years (P=0.011). Thus, high c-Src activity may identify a subset of DCIS with high risk of recurrence or progression to invasive cancer where therapeutics targeting c-Src may benefit this patient subset.

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Figures

Figure 1

Figure 1

(Ai–v) Experimental controls for Clone 28 immunohistochemistry of activated c-Src. Pellets of untreated or doxycycline treated HCT116 colon cancer cells that express a doxycycline-inducible, wild-type (wt) c-Src. High levels of activated c-Src were detected in doxycyline treated HCT116 colon cancer cells harbouring the doxycycline-inducible wt c-Src (Aiii). Detectable but lower levels of active c-Src were detected in these HCT116 cells in the absence of doxycyline treatment (Aii). Induction of wt c-Src was independently confirmed by western blotting using an anti Src[pY418] antibody specific for autophosphorylated active c-Src (Figure 1A insert. No significant immunoreactivity was detected in HCT116 cells analysed by mouse IgG2a, which served as a negative control (Ai). Figure 1A(iv) shows a section of a MDA MB231 tumour xenograft negative control (IgG2A) and 1A(v) shows clone positive staining with Clone 28 in this xenograft indicative of high levels of activated c-Src. (Bi–iv) Immunohistochemistry for activated c-Src using clone 28 in normal breast epithelium (Bi), and DCIS tumours (Bii–iv). Low levels of activated c-Src in B(ii), moderate levels in B(iii) and high levels in B(iv). A higher level of activated c-Src was detected in DCIS tumours compared with normal breast. There was a positive correlation between the level of activated c-Src and tumour nuclear grade (P<0.0005). The scale bar equals 50 _μ_m.

Figure 2

Figure 2

In univariate analysis, Kaplain–Meier plot of cumulative local recurrence (DCIS and invasive breast carcinoma) for 129 patients with DCIS. Low-activated c-Src expressing DCIS tumours had a significant disease-free survival advantage over DCIS expressing moderate to high levels of activated c-Src.

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