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Clinicopathological Analysis of miRNA Expression in Breast Cancer Tissues by Using miRNA In Situ Hybridization
Published on: June 7, 2016
Suppressor of cytokine signalling gene expression is elevated in breast carcinoma
1CNRS 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.
Insights
Suppressors of Cytokine Signaling (SOCS) proteins, particularly CIS, are elevated in breast cancer, potentially promoting tumor growth and resistance to immune responses. This suggests CIS may be a specific molecular lesion in breast cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Cytokines are crucial for breast cell function, acting as trophic hormones and mediating anti-cancer defenses.
- Suppressors of Cytokine Signaling (SOCS) proteins regulate cellular sensitivity to cytokines.
- SOCS family members, including CIS, are inducible feedback inhibitors of cytokine signaling pathways.
Purpose of the Study:
- To investigate the expression of SOCS genes in breast carcinomas and cancer cell lines compared to normal tissues.
- To determine if SOCS/CIS expression is altered in breast cancer and its potential role in tumor progression.
Main Methods:
- Quantitative in situ hybridization to assess SOCS/CIS transcript levels in tumor and stromal tissues.
- Immunohistochemistry to evaluate SOCS/CIS protein expression in breast carcinomas.
- Immunoblotting to detect CIS protein levels in breast cancer cell lines.
- Reporter assays to investigate the functional role of CIS in ERK kinase activation.
Main Results:
- Elevated SOCS-1-3 and CIS proteins and transcripts were observed in both in situ and infiltrating ductal carcinomas compared to normal breast tissue.
- CIS transcript and protein levels were significantly increased in all tested breast cancer cell lines but not in control lines.
- Increased CIS expression in cancer lines correlated with activation of ERK kinases, suggesting a proliferative role.
- Elevated CIS expression may contribute to shutting down STAT 5 signaling, conferring cytokine resistance, and promoting proliferation via ERK kinases.
Conclusions:
- Increased CIS expression appears to be a specific molecular lesion in breast cancer.
- Elevated CIS may simultaneously impair trophic hormone signaling, reduce host cytokine defense, and enhance tumor cell proliferation through ERK activation.
- The in vivo elevation of SOCS genes could represent a host/tumor response or a reaction to autocrine/paracrine growth factors.
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