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Published on: October 27, 2020
Singleminded-2s (Sim2s) promotes delayed involution of the mouse mammary gland through suppression of Stat3 and NFκB
Kelly C Scribner1, Elizabeth A Wellberg, Richard P Metz
1Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-4458, USA.
Abstract:
Postlactational involution of the mammary gland provides a unique model to study breast cancer susceptibility and metastasis. We have shown that the short isoform of Singleminded-2s (Sim2s), a basic helix loop helix/PAS transcription factor, plays a role in promoting lactogenic differentiation, as well as maintaining mammary epithelial differentiation and malignancy. Sim2s is dynamically expressed during mammary gland development, with expression peaking during lactation, and decreasing in early involution. To determine the role of SIM2S in involution, we used transgenic mice expressing SIM2S under the mouse mammary tumor virus-Sim2s promoter. Overexpression of Sim2s in the mouse mammary gland resulted in delayed involution, indicated by a lower proportion of cleaved caspase-3-positive cells and slower reestablishment of the mammary fat pad. Immunohistochemical and quantitative RNA analysis showed a decrease in apoptotic markers and inflammatory response genes, and an increase in antiapoptotic genes, which were accompanied by inhibition of signal transducer and activator of transcription 3 activity. Microarray analysis confirmed that genes in the signal transducer and activator of transcription 3 signaling pathway were repressed by SIM2S expression, along with nuclear factor-κB and other key pathways involved in mammary gland development. Multiparous mouse mammary tumor virus-Sim2s females displayed a more differentiated phenotype compared with wild-type controls, characterized by enhanced β-casein expression and alveolar structures. Together, these results suggest a role for SIM2S in the normal involuting gland and identify potential downstream pathways regulated by SIM2S.
Insights
The short isoform of Singleminded-2s (Sim2s) delays mammary gland involution by inhibiting apoptosis and inflammatory gene expression. This transcription factor plays a key role in regulating mammary gland development and differentiation.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Biology
Background:
- Postlactational mammary gland involution is a critical process for studying breast cancer susceptibility.
- The short isoform of Singleminded-2s (Sim2s) is a transcription factor involved in mammary epithelial differentiation and malignancy.
- Sim2s expression naturally decreases during mammary gland involution.
Purpose of the Study:
- To investigate the role of Sim2s in the process of mammary gland involution.
- To elucidate the molecular mechanisms by which Sim2s influences involution.
Main Methods:
- Utilized transgenic mice overexpressing Sim2s under the mouse mammary tumor virus promoter.
- Conducted immunohistochemical and quantitative RNA analysis to assess involution markers.
- Performed microarray analysis to identify affected signaling pathways.
Main Results:
- Sim2s overexpression significantly delayed mammary gland involution, evidenced by reduced apoptosis and slower tissue remodeling.
- Downregulation of apoptotic and inflammatory markers, alongside upregulation of antiapoptotic genes, was observed.
- Inhibition of signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) signaling pathways was confirmed.
- Transgenic mice exhibited a more differentiated mammary gland phenotype with enhanced β-casein expression.
Conclusions:
- Sim2s plays a significant role in regulating mammary gland involution.
- Sim2s exerts its effects by modulating apoptotic, inflammatory, and key developmental signaling pathways, including STAT3 and NF-κB.
- These findings identify Sim2s as a potential target for understanding and potentially intervening in processes related to mammary gland involution and associated pathologies.
