1. Increased levels of active c-Src distinguish invasive from in situ lobular lesions
- Author
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Parry Guilford, Donghui Zou, David Perez, Ahmad Anjomshoaa, Bostjan Humar, Han-Seung Yoon, and Ryuji Fukuzawa
- Subjects
STAT3 Transcription Factor ,Pathology ,medicine.medical_specialty ,Lobular carcinoma ,Proto-Oncogene Proteins pp60(c-src) ,Breast Neoplasms ,Biology ,CXCR4 ,Aldehyde Dehydrogenase 1 Family ,Mesoderm ,Breast cancer ,Drug Delivery Systems ,Cancer stem cell ,Recurrence ,medicine ,Carcinoma ,Biomarkers, Tumor ,Humans ,Vimentin ,Cell Lineage ,Neoplasm Invasiveness ,skin and connective tissue diseases ,Medicine(all) ,Hyperplasia ,Carcinoma in situ ,Retinal Dehydrogenase ,Epithelial Cells ,Aldehyde Dehydrogenase ,medicine.disease ,Cadherins ,Neoplasm Proteins ,body regions ,Isoenzymes ,Carcinoma, Lobular ,Invasive lobular carcinoma ,Focal Adhesion Kinase 1 ,Cell Transdifferentiation ,Cancer research ,Disease Progression ,Neoplastic Stem Cells ,Female ,Carcinoma in Situ ,Research Article - Abstract
Introduction 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). 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. Methods Immunochemistry 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. Results Levels 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. Conclusions Our 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.
- Published
- 2009