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

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 ¼ 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.

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer

“…Madan et al (2006) subsequently showed that c-Src activation did not correlate with the development of invasive tumour properties but correlated with malignant transformation. In ductal carcinoma in situ, activated c-Src was found to correlate with high tumour grade, high proliferation and HER 2 positivity, suggesting that high c-Src activity may identify a subset of DCIS at risk of disease progression to invasive carcinoma (Wilson et al, 2006).…”

Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells

“…Interestingly, it has recently been reported that expression of activated Src is associated with a reduced recurrencefree survival in ductal carcinoma in situ [15]. Steroidinduced cellular responses involve activation of Src and, although the molecular pathways involved in these responses have yet to be fully defined, can involve growth factor receptor signalling.…”

The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis

“…Src kinases are potently transforming and tumorigenic when constitutively activated, and their activation is seen in many human tumor types, including breast cancers with or without HER2 overexpression (Ottenhoff-Kalff et al, 1992; Belsches-Jablonski et al, 2001; Reissig et al, 2001). An association between src activation and HER2 overexpression has been reported in pre-invasive carcinomas of the breast (Wilson et al, 2006). Mammary tumors that arise in MMTV-neu transgenic mice have activation of c-src and c-yes (Muthuswamy et al, 1994;Muthuswamy and Muller, 1995a).…”