Src Kinase Family Members Expression in Human Breast Tissue and Their Association to Clinical Outcome of Breast Cancer Patients.

Abstract

Abstract Background: There is a paucity in the literature about expression levels of Src kinase family members (SKFMs) in human breast tissue. The aim of this study was to assess m-RNA SKFM expression levels in human breast specimens and to assess protein expression of the most significant SKFMs in invasive breast cancer to establish their association to clinical outcome.Material and Methods: m-RNA expression of eight SKFMs (Src, Lck, Lyn, Fgr, Fyn, Hck, Blk, Yes) was assessed by quantitative real time PCR. IHC was performed using antibodies to c-Src, Y419Src, Lck and Lyn. Expression was assessed using the weighted histoscore method.Results: Cohort one consisted of 52 invasive breast cancers (M), 36 non-malignant (NM) and 10 normal (N) breast tissue samples. Median age of the patients was 60 years. Median size of breast cancer was 25mm (IQR 20-40mm). ER status was not significantly different between tissue types (p=0.50). Every SKFM expression was quantified in all tissue samples. Fyn was the most expressed SKFM in normal tissue and Lyn in the NM breast tissue. Blk was the least expressed SKFM in all breast tissues. In malignant breast tissue Src and Lyn were most expressed. Higher expression levels of Lck were observed in invasive breast cancers compared to NM and N (p=<0.001). SKFMs Lck and Lyn were higher expressed in ER negative compared to ER positive tumours. c-Src (p=0.01) and Fyn (p=0.03) were expressed at higher levels in lobular compared to ductal carcinomas. There were no correlations observed between c-Src and SKFMs in N breast tissue. However in NM and M tissue, all seven SKFMs correlated with c-Src expression; strongest correlation observed was with Lyn (p<0.001, c.c 0.805) and least with Yes (p=0.003, c.c.=0.489). No association was noticed between SKFM expression, tumour grade, size and LN positivity.Cohort two consisted of 320 patients with median follow-up of 6.3 years. Median age was 58 years (IQR 24-90). Median tumour size was 20mm (IQR 15-30mm). In both cohorts majority of the cancer specimens were pathologically graded as G2 and G3. 49% of the patients were axillary lymph node positive. High cytoplasmic Src and membrane Y419Src kinase expression levels were significantly associated with decreased disease specific survival (p=0.028, p=0.023). Lyn was not associated with survival at any cellular location. High membrane Lck expression was significantly associated with improved survival (p=0.039).Patient Cohort 2 Patient NumbersP valueAge<50 yrs810.351 >50 yrs239 Tumour typeDuctal2980.714 Lobular18 Others6 Grade1220.014 2152 3146 Size<20mm126<0.001 20-50mm173 >50mm21 ER statusPositive212<0.001 Negative108 PR statusPositive1520.006 Negative168 HER2 statusPositive550.010 Negative265 c-Src cytoplasmPositive1410.023 Negative179 Y419Src membranePositive1540.028 Negative166 Lck membranePositive140.039 Negative266 Discussion: All eight SKFMs are expressed in different breast tissues. In invasive breast cancer Src kinase is highest expressed and seems to have a negative impact on disease specific survival. Whereas, high membrane expression of Lck provides better clinical outcome in those breast cancer patients. Further investigations are required to determine underlying mechanisms for this observation. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6130.