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STAT5 confers lactogenic properties in breast tumorigenesis and restricts metastatic potential

Abstract

Signal transducer and activator of transcription 5 (STAT5) promotes cell survival and instigates breast tumor formation, and in the normal breast it also drives alveolar differentiation and lactogenesis. However, whether STAT5 drives a differentiated phenotype in breast tumorigenesis and therefore impacts cancer spread and metastasis is unclear. We found in two genetically engineered mouse models of breast cancer that constitutively activated Stat5a (Stat5aca) caused precancerous mammary epithelial cells to become lactogenic and evolve into tumors with diminished potential to metastasize. We also showed that STAT5aca reduced the migratory and invasive ability of human breast cancer cell lines in vitro. Furthermore, we demonstrated that STAT5aca overexpression in human breast cancer cells lowered their metastatic burden in xenografted mice. Moreover, RPPA, Western blotting, and studies of ChIPseq data identified several EMT drivers regulated by STAT5. In addition, bioinformatic studies detected a correlation between STAT5 activity and better prognosis of breast cancer patients. Together, we conclude that STAT5 activation during mammary tumorigenesis specifies a tumor phenotype of lactogenic differentiation, suppresses EMT, and diminishes potential for subsequent metastasis.

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Fig. 1: STAT5aca causes lactogenic differentiation in ErbB2ca-induced precancerous lesions and tumors, and it blocks lung metastases.
Fig. 2: STAT5aca causes functional differentiation of mammary tumors initiated by PIK3CAH1047R.
Fig. 3: STAT5aca restricts the metastatic potential of human breast tumor cells, and higher STAT5A levels are associated with better prognosis of patients.
Fig. 4: STAT5aca suppresses breast cancer EMT.

Data availability

Available upon request to liyi@bcm.edu.

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Acknowledgements

This work was supported by DOD CDMRP BC191649 & BC191646 (to YL). The authors thank the SPORE-funded (P50CA186784) Pathology Core Facility at the Breast Center for tissue processing and Dr. Gary Chamness for helpful comments on the manuscript; the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672), the NIH (P30 CA125123 and S10 RR024574) and the expert assistance of Joel M. Sederstrom; the Antibody-Based Proteomics Core (RPPA core) at Baylor College of Medicine funded by CPRIT Core Facility Award (RP210227) and P30 Cancer Center Support Grant (NCI-CA125123), NIH S10 instrument award (S10OD028648-01), and the expert help of Dr. Xuan Wang. The authors thank Le Ma for gifting reagents and Dr. Wen Bu for intellectual input. ML is supported by the Chinese Scholarship Council (CSC), AK was supported by T32-CA203690. JMR is supported by NIH016303. CJC is supported by NIH CA125123.

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ML, ATK, JD contributed to the experimental design, methodology, data acquisition and analysis. WJ and AAI contributed to data acquisition in animal work. CN and CG evaluated slides and provided pathological reports. FY, FP and CJC performed bio-informatic analyses. SGH supervised statistical analyses. ML, ATK, and YL wrote the manuscript. JMR, XHZ, XC, YND, SH, AS and ZF provided supervision. All authors read the manuscript, agreed with the content, and were given the opportunity to provide input.

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Correspondence to Yi Li.

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Lin, M., Ku, A.T., Dong, J. et al. STAT5 confers lactogenic properties in breast tumorigenesis and restricts metastatic potential. Oncogene 41, 5214–5222 (2022). https://doi.org/10.1038/s41388-022-02500-w

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