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Suppressor of cytokine signalling gene expression is elevated in breast carcinoma.

Raccurt M, Tam SP, Lau P, Mertani HC, Lambert A, Garcia-Caballero T, Li H, Brown RJ, McGuckin MA, Morel G, Waters MJ - Br. J. Cancer (2003)

Bottom Line: Recently, inducible feedback suppressors of cytokine signalling (SOCS/JAB/SSI) have been identified, which decrease cell sensitivity to cytokines.A potential proliferative role for CIS overexpression is supported by reports that CIS activates ERK kinases, and by strong induction in transient reporter assays with an ERK-responsive promoter.The in vivo elevation of SOCS gene expression may be part of the host/tumour response or a response to autocrine/paracrine GH and prolactin.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR 5123, Bât. Raphael Dubois, Université Claude Bernard-Lyon 1, 43 Blvd 11 Novembre 1918, F69622 Villeurbanne cedex, France.

ABSTRACT
Cytokines are important for breast cell function, both as trophic hormones and as mediators of host defense mechanisms against breast cancer. Recently, inducible feedback suppressors of cytokine signalling (SOCS/JAB/SSI) have been identified, which decrease cell sensitivity to cytokines. We examined the expression of SOCS genes in 17 breast carcinomas and 10 breast cancer lines, in comparison with normal tissue and breast lines. We report elevated expression of SOCS-1-3 and CIS immunoreactive proteins within in situ ductal carcinomas and infiltrating ductal carcinomas relative to normal breast tissue. Significantly increased expression of SOCS-1-3 and CIS transcripts was also shown by quantitative in situ hybridisation within both tumour tissue and reactive stroma. CIS transcript expression was elevated in all 10 cancer lines, but not in control lines. However, there was no consistent elevation of other SOCS transcripts. CIS protein was shown by immunoblot to be present in all cancer lines at increased levels, mainly as the 47 kDa ubiquitinylated form. A potential proliferative role for CIS overexpression is supported by reports that CIS activates ERK kinases, and by strong induction in transient reporter assays with an ERK-responsive promoter. The in vivo elevation of SOCS gene expression may be part of the host/tumour response or a response to autocrine/paracrine GH and prolactin. However, increased CIS expression in breast cancer lines appears to be a specific lesion, and could simultaneously shut down STAT 5 signalling by trophic hormones, confer resistance to host cytokines and increase proliferation through ERK kinases.

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Cellular expression of SOCS-1–3 and CIS mRNA in normal breast (A, C, D), in situ (E–G) and invasive (H–J) ductal breast carcinomas, evidenced by the presence of bright silver grains on emulsion-coated sections. On sections of normal breast tissue, basal levels of SOCS-1 (C) and CIS (D) were detected in normal epithelial cells and in scattered fibroblasts of the surrounding connective tissue. On sections from patients with in situ ductal carcinoma, expression of SOCS-1 (E), SOCS-2 (F) and CIS (G) transcripts was strongly associated with proliferative tumour cells (arrows) of the enlarged ducts, in concentric layers of fibroblastic cells (arrowheads) and in lymphocytes of inflammatory infiltrates (*). On sections from patients with invasive ductal carcinoma, gene expression of SOCS-1 (H), SOCS-3 (I) and CIS (J) was abundantly detected in the whole area of the tumour. The close association of cancerous cells and stromal cells prevents the precise identification of the positive cell component. No signal was observed when in situ hybridisation was performed with heterologous cDNA probe as a negative control on normal breast tissue (A) and invasive ductal carcinoma (B). Bar, 50 μm.
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fig2: Cellular expression of SOCS-1–3 and CIS mRNA in normal breast (A, C, D), in situ (E–G) and invasive (H–J) ductal breast carcinomas, evidenced by the presence of bright silver grains on emulsion-coated sections. On sections of normal breast tissue, basal levels of SOCS-1 (C) and CIS (D) were detected in normal epithelial cells and in scattered fibroblasts of the surrounding connective tissue. On sections from patients with in situ ductal carcinoma, expression of SOCS-1 (E), SOCS-2 (F) and CIS (G) transcripts was strongly associated with proliferative tumour cells (arrows) of the enlarged ducts, in concentric layers of fibroblastic cells (arrowheads) and in lymphocytes of inflammatory infiltrates (*). On sections from patients with invasive ductal carcinoma, gene expression of SOCS-1 (H), SOCS-3 (I) and CIS (J) was abundantly detected in the whole area of the tumour. The close association of cancerous cells and stromal cells prevents the precise identification of the positive cell component. No signal was observed when in situ hybridisation was performed with heterologous cDNA probe as a negative control on normal breast tissue (A) and invasive ductal carcinoma (B). Bar, 50 μm.

Mentions: Macroautoradiographic pattern of ISH of SOCS-1–3, CIS mRNA performed on sections of normal breast (A–E) and typical lesions of in situ (F–J) and invasive (K–O) ductal carcinomas. Semiquantitative expression of mRNA was performed on typical areas of the samples, as illustrated in B, G and L, after precise microscopic examination of the contiguous HPS-stained sections (A, F and K). The signal (dark areas) corresponds to different levels of SOCS and CIS genes expression. On adjacent sections of normal breast tissue, the signal obtained for the four genes is localised to the ducts and lobules (arrow) (B–E). On adjacent sections of in situ ductal carcinoma, the same intense signal is observed for the four genes and is localized to areas corresponding to enlarged ducts and periductal stroma reaction (arrows) (G–J). On adjacent sections of invasive ductal carcinoma, the increased density observed with the four probes encompasses the area corresponding to tumour cells infiltrating the cellular stroma (L–O). Thus, a more intense signal is seen specifically localised to the area of tumour invasion (arrow). Bar, 5 mm.


Suppressor of cytokine signalling gene expression is elevated in breast carcinoma.

Raccurt M, Tam SP, Lau P, Mertani HC, Lambert A, Garcia-Caballero T, Li H, Brown RJ, McGuckin MA, Morel G, Waters MJ - Br. J. Cancer (2003)

Cellular expression of SOCS-1–3 and CIS mRNA in normal breast (A, C, D), in situ (E–G) and invasive (H–J) ductal breast carcinomas, evidenced by the presence of bright silver grains on emulsion-coated sections. On sections of normal breast tissue, basal levels of SOCS-1 (C) and CIS (D) were detected in normal epithelial cells and in scattered fibroblasts of the surrounding connective tissue. On sections from patients with in situ ductal carcinoma, expression of SOCS-1 (E), SOCS-2 (F) and CIS (G) transcripts was strongly associated with proliferative tumour cells (arrows) of the enlarged ducts, in concentric layers of fibroblastic cells (arrowheads) and in lymphocytes of inflammatory infiltrates (*). On sections from patients with invasive ductal carcinoma, gene expression of SOCS-1 (H), SOCS-3 (I) and CIS (J) was abundantly detected in the whole area of the tumour. The close association of cancerous cells and stromal cells prevents the precise identification of the positive cell component. No signal was observed when in situ hybridisation was performed with heterologous cDNA probe as a negative control on normal breast tissue (A) and invasive ductal carcinoma (B). Bar, 50 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2394374&req=5

fig2: Cellular expression of SOCS-1–3 and CIS mRNA in normal breast (A, C, D), in situ (E–G) and invasive (H–J) ductal breast carcinomas, evidenced by the presence of bright silver grains on emulsion-coated sections. On sections of normal breast tissue, basal levels of SOCS-1 (C) and CIS (D) were detected in normal epithelial cells and in scattered fibroblasts of the surrounding connective tissue. On sections from patients with in situ ductal carcinoma, expression of SOCS-1 (E), SOCS-2 (F) and CIS (G) transcripts was strongly associated with proliferative tumour cells (arrows) of the enlarged ducts, in concentric layers of fibroblastic cells (arrowheads) and in lymphocytes of inflammatory infiltrates (*). On sections from patients with invasive ductal carcinoma, gene expression of SOCS-1 (H), SOCS-3 (I) and CIS (J) was abundantly detected in the whole area of the tumour. The close association of cancerous cells and stromal cells prevents the precise identification of the positive cell component. No signal was observed when in situ hybridisation was performed with heterologous cDNA probe as a negative control on normal breast tissue (A) and invasive ductal carcinoma (B). Bar, 50 μm.
Mentions: Macroautoradiographic pattern of ISH of SOCS-1–3, CIS mRNA performed on sections of normal breast (A–E) and typical lesions of in situ (F–J) and invasive (K–O) ductal carcinomas. Semiquantitative expression of mRNA was performed on typical areas of the samples, as illustrated in B, G and L, after precise microscopic examination of the contiguous HPS-stained sections (A, F and K). The signal (dark areas) corresponds to different levels of SOCS and CIS genes expression. On adjacent sections of normal breast tissue, the signal obtained for the four genes is localised to the ducts and lobules (arrow) (B–E). On adjacent sections of in situ ductal carcinoma, the same intense signal is observed for the four genes and is localized to areas corresponding to enlarged ducts and periductal stroma reaction (arrows) (G–J). On adjacent sections of invasive ductal carcinoma, the increased density observed with the four probes encompasses the area corresponding to tumour cells infiltrating the cellular stroma (L–O). Thus, a more intense signal is seen specifically localised to the area of tumour invasion (arrow). Bar, 5 mm.

Bottom Line: Recently, inducible feedback suppressors of cytokine signalling (SOCS/JAB/SSI) have been identified, which decrease cell sensitivity to cytokines.A potential proliferative role for CIS overexpression is supported by reports that CIS activates ERK kinases, and by strong induction in transient reporter assays with an ERK-responsive promoter.The in vivo elevation of SOCS gene expression may be part of the host/tumour response or a response to autocrine/paracrine GH and prolactin.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR 5123, Bât. Raphael Dubois, Université Claude Bernard-Lyon 1, 43 Blvd 11 Novembre 1918, F69622 Villeurbanne cedex, France.

ABSTRACT
Cytokines are important for breast cell function, both as trophic hormones and as mediators of host defense mechanisms against breast cancer. Recently, inducible feedback suppressors of cytokine signalling (SOCS/JAB/SSI) have been identified, which decrease cell sensitivity to cytokines. We examined the expression of SOCS genes in 17 breast carcinomas and 10 breast cancer lines, in comparison with normal tissue and breast lines. We report elevated expression of SOCS-1-3 and CIS immunoreactive proteins within in situ ductal carcinomas and infiltrating ductal carcinomas relative to normal breast tissue. Significantly increased expression of SOCS-1-3 and CIS transcripts was also shown by quantitative in situ hybridisation within both tumour tissue and reactive stroma. CIS transcript expression was elevated in all 10 cancer lines, but not in control lines. However, there was no consistent elevation of other SOCS transcripts. CIS protein was shown by immunoblot to be present in all cancer lines at increased levels, mainly as the 47 kDa ubiquitinylated form. A potential proliferative role for CIS overexpression is supported by reports that CIS activates ERK kinases, and by strong induction in transient reporter assays with an ERK-responsive promoter. The in vivo elevation of SOCS gene expression may be part of the host/tumour response or a response to autocrine/paracrine GH and prolactin. However, increased CIS expression in breast cancer lines appears to be a specific lesion, and could simultaneously shut down STAT 5 signalling by trophic hormones, confer resistance to host cytokines and increase proliferation through ERK kinases.

Show MeSH
Related in: MedlinePlus