Soft Microenvironments Induce Chemoresistance by Increasing Autophagy Downstream of Integrin-Linked Kinase.

TitleSoft Microenvironments Induce Chemoresistance by Increasing Autophagy Downstream of Integrin-Linked Kinase.
Publication TypeJournal Article
Year of Publication2020
AuthorsAnlas, AA, Nelson, CM
JournalCancer Res
Volume80
Issue19
Pagination4103-4113
Date Published2020 10 01
ISSN1538-7445
KeywordsAutophagy, Breast Neoplasms, Cell Line, Tumor, Drug Resistance, Neoplasm, Estrogen Receptor alpha, Female, Humans, Protein-Serine-Threonine Kinases, Selective Estrogen Receptor Modulators, Tamoxifen, Tumor Microenvironment
Abstract

<p>Breast cancer relapse can develop over the course of years as a result of dormant cancer cells that disseminate to secondary sites. These dormant cells are often resistant to conventional hormone and chemotherapy. Although recurrence is the main cause of death from cancer, microenvironmental factors that may influence resistance to therapy and duration of dormancy are largely unknown. Breast cancer relapse is often detected in tissues that are softer than the normal mammary gland or the primary breast tumor, such as bone marrow, brain, and lung. We therefore explored how stiffness of the microenvironment at secondary sites regulates tumor dormancy and the response of breast cancer cells to hormone and chemotherapy. In soft microenvironments reminiscent of metastatic sites, breast cancer cells were more resistant to the estrogen receptor modulator tamoxifen as a result of increased autophagy and decreased expression of estrogen receptor-α. Consistently, pharmacologic inhibition or genetic downregulation of autophagy increased the response of breast cancer cells to tamoxifen on soft substrata. In addition, autophagy was decreased downstream of integrin-linked kinase on stiff substrata. Altogether, our data show that tissue mechanics regulates therapeutic outcome and long-term survival of breast cancer cells by influencing autophagy. SIGNIFICANCE: These findings characterize the persistence of dormant cells at metastatic sites, where soft microenvironments downregulate estrogen receptor expression and upregulate autophagy, thereby promoting therapy resistance in breast cancer cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/19/4103/F1.large.jpg...

DOI10.1158/0008-5472.CAN-19-4021
Alternate JournalCancer Res
PubMed ID33008805
PubMed Central IDPMC7534696
Grant ListR01 CA187692 / CA / NCI NIH HHS / United States
U01 CA214292 / CA / NCI NIH HHS / United States