Altered molecular pathways decides the treatment outcome of Hsp90 inhibitors against breast cancer cells.

Abstract

The altered molecular pathways in response to chemotherapeutic interventions impose limitations on breast cancer treatments. Therefore, understanding the outcome of these alternative pathways may help in improving the chemotherapy. In this study, using hormone responsive and hormone independent breast cancer cells, MCF-7 and MDAMB-231 respectively, we studied some of the molecular pathways that contribute to cancer progression. Since the cancer chaperone, Hsp90 inhibitors have entered the clinical trials, we used Hsp90 inhibitor, 17AAG to examine the outcome of altered molecular pathways. The observed differential sensitivity in MCF7 and MDAMB-231 cells to 17AAG treatment is then attributed to both tumor microenvironment mediated by hypoxia and acquired alterations in the endogenous stem cell pool. Interestingly, tumor cells are able to retain epithelial characteristics in addition to gaining mesenchymal characteristics in response to 17AAG treatment. We observed MCF-7 cells exhibiting induced cellular differentiation, whereas MDAMB-231 cells exhibiting reduced cellular differentiation in response to 17AAG treatment. These changes are subsequently found to be the sporadic outcome of altered epigenetic landscape. The mice tumor xenograft studies have revealed that decreased metastatic potential of MCF-7 and increased metastatic potential with altered homing properties of MDAMB-231 are the outcome of altered molecular pathways. Our findings expose the interference of altered molecular pathways influencing the therapeutic outcome.

• Authors: Naga Gowthami Vykuntham, Sourabh Suran, Satish Siripini, Samu John, Pankaj Kumar, Khanderao Paithankar, Sreedhar Amere Subbarao
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 65 Pg. 104828 (Jun 2020) ISSN: 1879-3177 [Electronic] England
• PMID: 32184171 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• tanespimycin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzoquinones (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Epigenesis, Genetic
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Lactams, Macrocyclic (pharmacology, therapeutic use)
• Mammary Neoplasms, Experimental (drug therapy, genetics)
• Mice, Nude
• Treatment Outcome
• Tumor Microenvironment (drug effects)