Research article

Increased levels of active c-Src distinguish invasive from in situ lobular lesions

Donghui Zou¹ , Han-Seung Yoon² , Ahmad Anjomshoaa¹ , David Perez³ , Ryuji Fukuzawa¹ , Parry Guilford¹ and Bostjan Humar¹

¹  Cancer Genetics Laboratory, Biochemistry Department, University of Otago, 710 Cumberland St, Dunedin 9054, Aotearoa New Zealand

²  Pathology Department, University of Otago, 201 Great King St, Dunedin 9016, Aotearoa New Zealand

³  Oncology Department, University of Otago, Dunedin Hospital, 201 Great King St, Dunedin 9016, Aotearoa New Zealand

author email corresponding author email

Breast Cancer Research 2009, 11:R45doi:10.1186/bcr2332

Published:	7 July 2009

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.