Increased levels of active c-Src distinguish invasive from in situ lobular lesions.
BACKGROUND
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.
Zou
Donghui
D
Cancer Genetics Laboratory, Biochemistry Department, University of Otago, 710 Cumberland St, Dunedin 9054, Aotearoa New Zealand. donghui.zou@otago.ac.nz
Yoon
Han-Seung
HS
Anjomshoaa
Ahmad
A
Perez
David
D
Fukuzawa
Ryuji
R
Guilford
Parry
P
Humar
Bostjan
B
D000444:Aldehyde Dehydrogenase / Q000032:analysis; D000080924:Aldehyde Dehydrogenase 1 Family; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000175:diagnosis / Q000473:pathology; D015820:Cadherins / Q000032:analysis; D002278:Carcinoma in Situ / Q000737:chemistry* / Q000175:diagnosis / Q000473:pathology; D018275:Carcinoma, Lobular / Q000737:chemistry* / Q000175:diagnosis / Q000473:pathology; D019070:Cell Lineage; D054338:Cell Transdifferentiation; D018450:Disease Progression; D016503:Drug Delivery Systems; D004847:Epithelial Cells / Q000737:chemistry / Q000473:pathology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000032:analysis; D006801:Humans; D006965:Hyperplasia; D007527:Isoenzymes / Q000032:analysis; D008648:Mesoderm / Q000473:pathology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis*; D014411:Neoplastic Stem Cells / Q000737:chemistry; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000032:analysis*; D012008:Recurrence; D050697:Retinal Dehydrogenase; D050796:STAT3 Transcription Factor / Q000032:analysis; D014746:Vimentin / Q000032:analysis
D014408:Biomarkers, Tumor; D015820:Cadherins; D007527:Isoenzymes; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014746:Vimentin; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src)