Article ; Online: Biomechanical regulation of breast cancer metastasis and progression.
2021 Volume 11, Issue 1, Page(s) 9838
Abstract: Physical activity has been consistently linked to decreased incidence of breast cancer and a substantial increase in the length of survival of patients with breast cancer. However, the understanding of how applied physical forces directly regulate breast ...
| Abstract | Physical activity has been consistently linked to decreased incidence of breast cancer and a substantial increase in the length of survival of patients with breast cancer. However, the understanding of how applied physical forces directly regulate breast cancer remains limited. We investigated the role of mechanical forces in altering the chemoresistance, proliferation and metastasis of breast cancer cells. We found that applied mechanical tension can dramatically alter gene expression in breast cancer cells, leading to decreased proliferation, increased resistance to chemotherapeutic treatment and enhanced adhesion to inflamed endothelial cells and collagen I under fluidic shear stress. A mechanistic analysis of the pathways involved in these effects supported a complex signaling network that included Abl1, Lck, Jak2 and PI3K to regulate pro-survival signaling and enhancement of adhesion under flow. Studies using mouse xenograft models demonstrated reduced proliferation of breast cancer cells with orthotopic implantation and increased metastasis to the skull when the cancer cells were treated with mechanical load. Using high throughput mechanobiological screens we identified pathways that could be targeted to reduce the effects of load on metastasis and found that the effects of mechanical load on bone colonization could be reduced through treatment with a PI3Kγ inhibitor. |
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| MeSH term(s) | Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Biomechanical Phenomena ; Breast/pathology ; Breast Neoplasms/diagnosis ; Breast Neoplasms/drug therapy ; Breast Neoplasms/pathology ; Cell Adhesion/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Disease Progression ; Drug Resistance, Neoplasm/drug effects ; Female ; Gene Expression Regulation, Neoplastic ; Human Umbilical Vein Endothelial Cells ; Humans ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors/pharmacology ; Phosphoinositide-3 Kinase Inhibitors/therapeutic use ; Signal Transduction/drug effects ; Stress, Mechanical ; X-Ray Microtomography ; Xenograft Model Antitumor Assays |
| Chemical Substances | Phosphoinositide-3 Kinase Inhibitors |
| Language | English |
| Publishing date | 2021-05-10 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. |
| ZDB-ID | 2615211-3 |
| ISSN | 2045-2322 ; 2045-2322 |
| ISSN (online) | 2045-2322 |
| ISSN | 2045-2322 |
| DOI | 10.1038/s41598-021-89288-z |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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