Heat shock protein 72 supports extracellular matrix production in metastatic mammary tumors

Benjamin J Lang; Kristina M Holton; Martin E Guerrero-Gimenez; Yuka Okusha; Patrick T Magahis; Amy Shi; Mary Neguse; Shreya Venkatesh; Anh M Nhu; Jason E Gestwicki; Stuart K Calderwood

doi:10.1016/j.cstres.2024.04.006

Heat shock protein 72 supports extracellular matrix production in metastatic mammary tumors

Cell Stress Chaperones. 2024 May 3;29(3):456-471. doi: 10.1016/j.cstres.2024.04.006. Online ahead of print.

Authors

Affiliations

¹ Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: ben.lang.170@gmail.com.
² Research Computing, Harvard Medical School, Boston, MA, USA.
³ Institute of Biochemistry and Biotechnology, School of Medicine, National University of Cuyo, Mendoza, Argentina.
⁴ Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁵ Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: stukcalderwood@gmail.com.

Abstract

This study identified tumorigenic processes most dependent on murine heat shock protein 72 (HSP72) in the mouse mammary tumor virus-PyMT mammary tumor model, which give rise to spontaneous mammary tumors that exhibit HSP72-dependent metastasis to the lung. RNA-seq expression profiling of Hspa1a/Hspa1b (Hsp72) WT and Hsp72^-/- primary mammary tumors discovered significantly lower expression of genes encoding components of the extracellular matrix (ECM) in Hsp72 knockout mammary tumors compared to WT controls. In vitro studies found that genetic or chemical inhibition of HSP72 activity in cultured collagen-expressing human or murine cells also reduces mRNA and protein levels of COL1A1 and several other ECM-encoding genes. In search of a possible mechanistic basis for this relationship, we found HSP72 to support the activation of the tumor growth factor-β-suppressor of mothers against decapentaplegic-3 signaling pathway and evidence of suppressor of mothers against decapentaplegic-3 and HSP72 coprecipitation, suggesting potential complex formation. Human COL1A1 mRNA expression was found to have prognostic value for HER2+ breast tumors over other breast cancer subtypes, suggesting a possible human disease context where targeting HSP72 may have a therapeutic rationale. Analysis of human HER2+ breast tumor gene expression data using a gene set comprising ECM-related gene and protein folding-related gene as an input to the statistical learning algorithm, Galgo, found a subset of these genes that can collectively stratify patients by relapse-free survival, further suggesting a potential interplay between the ECM and protein-folding genes may contribute to tumor progression.

Keywords: COL1A1; Collagen; Extracellular matrix (ECM); HER2; HSP70; Heat shock protein 72 (HSP72).