Abstract
Breast cancer is hallmarked by phenotypic transitions enabling abnormal cell proliferation and invasion. The stress-protective transcription factor heat shock factor 2 (HSF2) is associated with cancer, but its function in breast carcinogenesis remains poorly understood. Analysis of human breast tumor samples and mouse in vivo xenografts uncovered that HSF2 expression and activity undergo dynamic changes as a function of tumor progression. HSF2 expression, nuclear localization, and coexpression with the proliferation marker Ki67 are increased in ductal carcinoma in situ (DCIS), suggesting that HSF2 designates hyperplastic cells underlying tumor expansion. In mouse xenografts, HSF2 localization switches from nuclear to cytoplasmic upon DCIS-to-invasive transition. Using cell-based models, we identify canonical transforming growth factor–β (TGF-β) signaling as the molecular mechanism regulating HSF2. TGF-β–mediated down-regulation of HSF2 allowed acquisition of an invasive cell phenotype, which was counteracted by ectopic HSF2. Together, we propose that HSF2 acts as a stage-specific switch between proliferation and invasion in breast cancer.
| Original language | English |
|---|---|
| Article number | eady1289 |
| Journal | Science Advances |
| Volume | 11 |
| Issue number | 36 |
| DOIs | |
| Publication status | Published - Sept 2025 |
| MoE publication type | A1 Journal article-refereed |
Funding
Acknowledgments: We thank the patients that voluntarily donated their tissue to this study and the clinical staff of turku University hospital. We thank all members of the Sistonen laboratory for valuable comments and critical review of the manuscript. We thank J. ivaska for kindly providing the McF10-dciS.com xenograft samples and M. l. Mendillo for the MdA-MB-231 hSF1-KO cell line. M. Peurla is acknowledged for assistance with the image analysis. We thank i. Paatero, the head of Zebrafish Facility at turku Bioscience centre, for assistance with zebrafish xenograft experiments. the Finnish Functional Genomics centre is acknowledged for library preparation and sequencing of RnA-seq samples. the Finnish Functional Genomics centre is supported by the University of turku, Åbo Akademi University, and Biocenter Finland. the tissue samples were prepared at histocore (institute of Biomedicine, University of turku), and microscopy analyses were conducted at the cell imaging and cytometry core facility (turku Bioscience, University of turku and Åbo Akademi University, and Biocenter Finland). Funding: this work was supported by the Research council of Finland (S.G., e.P., and l.S.); Sigrid Jusélius Foundation (e.P. and l.S.); cancer Foundation Finland (e.P. and l.S.); Jane and Aatos erkko Foundation (e.P. and l.S.); Åbo Akademi University funded doctoral Position (J.c.P.); the Finnish cultural Foundation, Kymenlaakso Regional Fund (J.c.P.); turku doctoral Program in Molecular Medicine (O.P.); Swedish cultural Foundation (M.c.P.); K. Albin Johansson’s Foundation (h.S.e.h., M.c.P., and A.J.d.S.); Magnus ehrnrooth Foundation (A.J.d.S.); the Medical Research Foundation liv och hälsa (A.J.d.S. and l.S.); Finnish cultural Foundation (A.J.d.S. and S.G.); the Finnish cultural Foundation, lapland Regional Fund (J.J.); lapland hospital district Research Grant (J.J.); and the hospital district of Southwestern Finland (e.P.). Author contributions: conceptualization: J.c.P., M.c.P., A.J.d.S., S.P., P.B., P.h., e.P., J.J., and l.S. data curation: M.c.P., A.J.d.S., e.P., and l.S. Formal analysis: J.c.P., O.P., h.S.e.h., M.c.P., and A.J.d.S. Funding acquisition: J.c.P., O.P., M.c.P., e.P., J.J., and l.S. investigation: J.c.P., O.P., M.c.P., S.P., and e.P. Methodology: J.c.P., M.c.P., A.J.d.S., S.G., and e.P. Project administration: J.c.P., M.c.P., e.P., and l.S. Resources: M.c.P., P.B., P.h., e.P., and l.S. Supervision: J.c.P., M.c.P., e.P., and l.S. validation: J.c.P., O.P., M.c.P., and S.P. visualization: J.c.P., O.P., h.S.e.h., M.c.P., e.P., J.J., and l.S. Writing—original draft: J.c.P., M.c.P., e.P., J.J., and l.S. Writing—review and editing: J.c.P., O.P., M.c.P., A.J.d.S., S.P., P.h., e.P., J.J., and l.S. Competing interests: the authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. the original data are available at the Gene expression Omnibus (GeO) database under accession number GSe211020. We thank the patients that voluntarily donated their tissue to this study and the clinical staff of Turku University Hospital. We thank all members of the Sistonen Laboratory for valuable comments and critical review of the manuscript. We thank J. Ivaska for kindly providing the MCF10-DCIS.com xenograft samples and M. L. Mendillo for the MDA-MB-231 HSF1-KO cell line. M. Peurla is acknowledged for assistance with the image analysis. We thank I. Paatero, the head of Zebrafish Facility at Turku Bioscience Centre, for assistance with zebrafish xenograft experiments. The Finnish Functional Genomics Centre is acknowledged for library preparation and sequencing of RNA-seq samples. The Finnish Functional Genomics Centre is supported by the University of Turku, Åbo Akademi University, and Biocenter Finland. The tissue samples were prepared at Histocore (Institute of Biomedicine, University of Turku), and microscopy analyses were conducted at The Cell Imaging and Cytometry Core facility (Turku Bioscience, University of Turku and Åbo Akademi University, and Biocenter Finland). This work was supported by the Research Council of Finland (S.G., E.P., and L.S.); Sigrid Jusélius Foundation (E.P. and L.S.); Cancer Foundation Finland (E.P. and L.S.); Jane and Aatos Erkko Foundation (E.P. and L.S.); Åbo Akademi University funded Doctoral Position (J.C.P.); The Finnish Cultural Foundation, Kymenlaakso Regional Fund (J.C.P.); Turku Doctoral Program in Molecular Medicine (O.P.); Swedish Cultural Foundation (M.C.P.); K. Albin Johansson’s Foundation (H.S.E.H., M.C.P., and A.J.D.S.); Magnus Ehrnrooth Foundation (A.J.D.S.); The Medical Research Foundation Liv och Hälsa (A.J.D.S. and L.S.); Finnish Cultural Foundation (A.J.D.S. and S.G.); The Finnish Cultural Foundation, Lapland Regional Fund (J.J.); Lapland Hospital District Research Grant (J.J.); and The Hospital District of Southwestern Finland (E.P.).
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