Abstract
IntroductionMounting molecular evidence suggests that invasive lobular carcinoma (ILC) is developing from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). However, little is known about the mechanisms promoting the progression of lobular breast cancer (LBC) to invasive disease. Here, we investigated whether c-Src kinase, an established inducer of invasive states, contributes to the progression from ALH/LCIS to ILC.MethodsImmunochemistry for c-Src and other cancer-related molecules was performed on archived tissue specimens from 57 LBC patients. Relative c-Src activity was estimated by comparing fluorescence intensity of ILC with that of adjacent ALH/LCIS and nonneoplastic epithelia after staining with an antibody against active c-Src. Expression of active c-Src was correlated with markers of invasion and malignancy and with relapse among LBC patients.ResultsLevels of activated c-Src were increased in ILC relative to ALH/LCIS (1.63-fold ± 0.24 SD) and nonneoplastic epithelia (1.47 ± 0.18 SD). Increased c-Src levels correlated with the activation of c-Src downstream targets (Fak, Stat-3) and the expression of mesenchymal markers. ILC cells with activated c-Src co-expressed metastatic markers (Opn, Cxcr4) and included cells positive for the cancer stem cell marker Aldh1. A tendency for high c-Src levels (P = 0.072) was observed among the seven LBC patients with relapsed disease.ConclusionsOur data indicate elevated c-Src activity in ILC relative to noninvasive neoplastic tissue. The associated molecular changes suggest that c-Src promotes LBC invasiveness by inducing an epithelial-mesenchymal transition. Therefore, c-Src antagonists might counteract the acquisition of invasiveness during LBC progression. Inhibition of c-Src may also affect ILC cells thought to have a high metastatic potential and to be capable of initiating/maintaining tumor growth. Together with the possible association between high c-Src levels and disease recurrence, our findings encourage the evaluation of c-Src antagonists for the treatment of LBC.
Highlights
Mounting molecular evidence suggests that invasive lobular carcinoma (ILC) is developing from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS)
C-Src activity is increased in ILC compared with LCIS and nonneoplastic mammary epithelium To assess the activity of c-Src in ILC relative to in situ lesions and nonneoplastic epithelium, immunochemistry with the clone 28 antibody was performed on Formalin-fixed paraffin embedded (FFPE) sections from 57 lobular breast cancer (LBC) patients
To obtain an objective measure for the relative c-Src activity, fluorescence intensity was determined across ILC, LCIS, and epithelial components, and intensity ratios were calculated for each sample separately
Summary
Mounting molecular evidence suggests that invasive lobular carcinoma (ILC) is developing from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). Antagonists of the kinase c-Src are gaining increased attention as chemotherapeutic agents in breast cancer Both in vitro studies and transgenic models suggest a central role or even a requirement for c-Src during the development and progression of breast disease (reviewed in [1,2,3]). Src inhibitors is that they may be active against triple-negative and otherwise resistant breast cancer, for which existing therapy is inefficient [2,3] These data are based largely on the major breast cancer histotype, ductal carcinoma. Whether c-Src has a role in lobular breast carcinoma (LBC, which includes some of the triple-negative tumors) remains to be shown This is a considerable gap in knowledge, because the clinical management is more challenging for LBC compared with ductal disease, and the increase in LBC inci-
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