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Breast cancer patients' clinical outcome measures are associated with Src kinase family member expression.

Elsberger B, Fullerton R, Zino S, Jordan F, Mitchell TJ, Brunton VG, Mallon EA, Shiels PG, Edwards J - Br. J. Cancer (2010)

Bottom Line: High cytoplasmic Src kinase protein expression was significantly associated with decreased disease-specific survival.High membrane Lck expression was significantly associated with improved survival.Membrane expression of Lck was associated with improved clinical outcome.

View Article: PubMed Central - PubMed

Affiliation: Western Infirmary Glasgow, Section of Surgery, Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, Level 2, McGregor Building, Dumbarton Road, Glasgow G11 6NT, UK.

ABSTRACT

Background: This study determined mRNA expression levels for Src kinase family (SFK) members in breast tissue specimens and assessed protein expression levels of prominent SFK members in invasive breast cancer to establish associations with clinical outcome. Ki67 was investigated to determine association between SFK members and proliferation.

Methods: The mRNA expression levels were assessed for eight SFK members by quantitative real-time PCR. Immunohistochemistry was performed for c-Src, Lyn, Lck and Ki67.

Results: mRNA expression was quantified in all tissue samples. SRC and LYN were the most highly expressed in malignant tissue. LCK was more highly expressed in oestrogen receptor (ER)-negative, compared with ER-positive tumours. High cytoplasmic Src kinase protein expression was significantly associated with decreased disease-specific survival. Lyn was not associated with survival at any cellular location. High membrane Lck expression was significantly associated with improved survival. Ki67 expression correlated with tumour grade and nuclear c-Src, but was not associated with survival.

Conclusions: All eight SFK members were expressed in different breast tissues. Src kinase was highest expressed in breast cancer and had a negative impact on disease-specific survival. Membrane expression of Lck was associated with improved clinical outcome. High expression of Src kinase correlated with high proliferation.

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Images of immunohistochemistry (IHC) for each antibody. (A–C) Breast cancer tissue stained with c-Src antibody (1 : 200, Cell Signalling). (A) An overview of a 0.6 mm core of the breast cancer tissue microarray, demonstrating no stromal staining, weak cytoplasmic, none and weak nuclear staining; magnification × 10. (B) Weak cytoplasmic, none and weak nuclear and weak membrane staining; magnification × 100. (C) Negative staining of stroma and tumour tissue; magnification × 100. (D–F) Breast cancer tissue stained with Lyn antibody (1 : 5, BD Biosciences). (D) An overview of a 0.6 mm core of the breast cancer tissue microarray, demonstrating no stromal staining, weak cytoplasmic, none and weak nuclear staining; magnification × 10. (E) Weak cytoplasmic, none and weak nuclear staining; magnification × 100. (F) No stromal staining, weak cytoplasmic, none, weak and moderate nuclear staining; magnification × 100. (G–I) Breast cancer tissue stained with Lck antibody (1 : 50, Cell Signalling). (G) Strong staining of tonsil with Lck (positive control); magnification × 2. (H) Negative staining of stroma and tumour tissue; magnification × 100. (I) Weak cytoplasmic and weak membrane staining; magnification × 100. (J–M) Ki67 staining of invasive breast cancer specimen (1 : 150, DAKO). (J) Negative staining of stroma and tumour tissue; magnification × 100. (K) Ki67 staining classified as weak staining; magnification × 100. (L) Ki67 staining classified as moderate staining; magnification × 100. (M) Ki67 staining classified as strong staining; magnification × 100.
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fig3: Images of immunohistochemistry (IHC) for each antibody. (A–C) Breast cancer tissue stained with c-Src antibody (1 : 200, Cell Signalling). (A) An overview of a 0.6 mm core of the breast cancer tissue microarray, demonstrating no stromal staining, weak cytoplasmic, none and weak nuclear staining; magnification × 10. (B) Weak cytoplasmic, none and weak nuclear and weak membrane staining; magnification × 100. (C) Negative staining of stroma and tumour tissue; magnification × 100. (D–F) Breast cancer tissue stained with Lyn antibody (1 : 5, BD Biosciences). (D) An overview of a 0.6 mm core of the breast cancer tissue microarray, demonstrating no stromal staining, weak cytoplasmic, none and weak nuclear staining; magnification × 10. (E) Weak cytoplasmic, none and weak nuclear staining; magnification × 100. (F) No stromal staining, weak cytoplasmic, none, weak and moderate nuclear staining; magnification × 100. (G–I) Breast cancer tissue stained with Lck antibody (1 : 50, Cell Signalling). (G) Strong staining of tonsil with Lck (positive control); magnification × 2. (H) Negative staining of stroma and tumour tissue; magnification × 100. (I) Weak cytoplasmic and weak membrane staining; magnification × 100. (J–M) Ki67 staining of invasive breast cancer specimen (1 : 150, DAKO). (J) Negative staining of stroma and tumour tissue; magnification × 100. (K) Ki67 staining classified as weak staining; magnification × 100. (L) Ki67 staining classified as moderate staining; magnification × 100. (M) Ki67 staining classified as strong staining; magnification × 100.

Mentions: Each cellular location was independently assessed for Src kinase expression levels. A total of 48% of tumours exhibited nuclear expression, 61% cytoplasmic and 41% membrane (Figure 3A–C). Tumours were subdivided into those with high (above the median) or low (below or equal to the median) expression. The χ2-analysis demonstrated that grade and HER2 status positively correlated with cytoplasmic c-Src expression (Table 3). The ER and PgR status correlated negatively with cytoplasmic and membrane c-Src expression (Table 3). c-Src expression at each cellular location correlated with HER2 status (Table 3) and with each other (Table 4). On univariate analysis, neither membrane nor nuclear c-Src expression was associated with disease-specific survival. High cytoplasmic c-Src kinase expression was significantly associated with shorter disease-specific survival (P=0.013; Figure 4A), but was not independent in multivariate analysis (Table 2). Those patients with high cytoplasmic c-Src expression had a median survival of 12.2 years (IQR 10.0–14.4) compared with those with low expression, with median survival of 15.6 years (IQR 13.9–17.3).


Breast cancer patients' clinical outcome measures are associated with Src kinase family member expression.

Elsberger B, Fullerton R, Zino S, Jordan F, Mitchell TJ, Brunton VG, Mallon EA, Shiels PG, Edwards J - Br. J. Cancer (2010)

Images of immunohistochemistry (IHC) for each antibody. (A–C) Breast cancer tissue stained with c-Src antibody (1 : 200, Cell Signalling). (A) An overview of a 0.6 mm core of the breast cancer tissue microarray, demonstrating no stromal staining, weak cytoplasmic, none and weak nuclear staining; magnification × 10. (B) Weak cytoplasmic, none and weak nuclear and weak membrane staining; magnification × 100. (C) Negative staining of stroma and tumour tissue; magnification × 100. (D–F) Breast cancer tissue stained with Lyn antibody (1 : 5, BD Biosciences). (D) An overview of a 0.6 mm core of the breast cancer tissue microarray, demonstrating no stromal staining, weak cytoplasmic, none and weak nuclear staining; magnification × 10. (E) Weak cytoplasmic, none and weak nuclear staining; magnification × 100. (F) No stromal staining, weak cytoplasmic, none, weak and moderate nuclear staining; magnification × 100. (G–I) Breast cancer tissue stained with Lck antibody (1 : 50, Cell Signalling). (G) Strong staining of tonsil with Lck (positive control); magnification × 2. (H) Negative staining of stroma and tumour tissue; magnification × 100. (I) Weak cytoplasmic and weak membrane staining; magnification × 100. (J–M) Ki67 staining of invasive breast cancer specimen (1 : 150, DAKO). (J) Negative staining of stroma and tumour tissue; magnification × 100. (K) Ki67 staining classified as weak staining; magnification × 100. (L) Ki67 staining classified as moderate staining; magnification × 100. (M) Ki67 staining classified as strong staining; magnification × 100.
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fig3: Images of immunohistochemistry (IHC) for each antibody. (A–C) Breast cancer tissue stained with c-Src antibody (1 : 200, Cell Signalling). (A) An overview of a 0.6 mm core of the breast cancer tissue microarray, demonstrating no stromal staining, weak cytoplasmic, none and weak nuclear staining; magnification × 10. (B) Weak cytoplasmic, none and weak nuclear and weak membrane staining; magnification × 100. (C) Negative staining of stroma and tumour tissue; magnification × 100. (D–F) Breast cancer tissue stained with Lyn antibody (1 : 5, BD Biosciences). (D) An overview of a 0.6 mm core of the breast cancer tissue microarray, demonstrating no stromal staining, weak cytoplasmic, none and weak nuclear staining; magnification × 10. (E) Weak cytoplasmic, none and weak nuclear staining; magnification × 100. (F) No stromal staining, weak cytoplasmic, none, weak and moderate nuclear staining; magnification × 100. (G–I) Breast cancer tissue stained with Lck antibody (1 : 50, Cell Signalling). (G) Strong staining of tonsil with Lck (positive control); magnification × 2. (H) Negative staining of stroma and tumour tissue; magnification × 100. (I) Weak cytoplasmic and weak membrane staining; magnification × 100. (J–M) Ki67 staining of invasive breast cancer specimen (1 : 150, DAKO). (J) Negative staining of stroma and tumour tissue; magnification × 100. (K) Ki67 staining classified as weak staining; magnification × 100. (L) Ki67 staining classified as moderate staining; magnification × 100. (M) Ki67 staining classified as strong staining; magnification × 100.
Mentions: Each cellular location was independently assessed for Src kinase expression levels. A total of 48% of tumours exhibited nuclear expression, 61% cytoplasmic and 41% membrane (Figure 3A–C). Tumours were subdivided into those with high (above the median) or low (below or equal to the median) expression. The χ2-analysis demonstrated that grade and HER2 status positively correlated with cytoplasmic c-Src expression (Table 3). The ER and PgR status correlated negatively with cytoplasmic and membrane c-Src expression (Table 3). c-Src expression at each cellular location correlated with HER2 status (Table 3) and with each other (Table 4). On univariate analysis, neither membrane nor nuclear c-Src expression was associated with disease-specific survival. High cytoplasmic c-Src kinase expression was significantly associated with shorter disease-specific survival (P=0.013; Figure 4A), but was not independent in multivariate analysis (Table 2). Those patients with high cytoplasmic c-Src expression had a median survival of 12.2 years (IQR 10.0–14.4) compared with those with low expression, with median survival of 15.6 years (IQR 13.9–17.3).

Bottom Line: High cytoplasmic Src kinase protein expression was significantly associated with decreased disease-specific survival.High membrane Lck expression was significantly associated with improved survival.Membrane expression of Lck was associated with improved clinical outcome.

View Article: PubMed Central - PubMed

Affiliation: Western Infirmary Glasgow, Section of Surgery, Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, Level 2, McGregor Building, Dumbarton Road, Glasgow G11 6NT, UK.

ABSTRACT

Background: This study determined mRNA expression levels for Src kinase family (SFK) members in breast tissue specimens and assessed protein expression levels of prominent SFK members in invasive breast cancer to establish associations with clinical outcome. Ki67 was investigated to determine association between SFK members and proliferation.

Methods: The mRNA expression levels were assessed for eight SFK members by quantitative real-time PCR. Immunohistochemistry was performed for c-Src, Lyn, Lck and Ki67.

Results: mRNA expression was quantified in all tissue samples. SRC and LYN were the most highly expressed in malignant tissue. LCK was more highly expressed in oestrogen receptor (ER)-negative, compared with ER-positive tumours. High cytoplasmic Src kinase protein expression was significantly associated with decreased disease-specific survival. Lyn was not associated with survival at any cellular location. High membrane Lck expression was significantly associated with improved survival. Ki67 expression correlated with tumour grade and nuclear c-Src, but was not associated with survival.

Conclusions: All eight SFK members were expressed in different breast tissues. Src kinase was highest expressed in breast cancer and had a negative impact on disease-specific survival. Membrane expression of Lck was associated with improved clinical outcome. High expression of Src kinase correlated with high proliferation.

Show MeSH
Related in: MedlinePlus