Cytosolic Hsp90α and its mitochondrial isoform Trap1 are differentially required in a breast cancer model

Abstract

The Hsp90 family of molecular chaperones includes the cytosolic isoforms Hsp90a and Hsp90β and the mitochondrial isoform Trap1. Hsp90a/βsupport a large number of client proteins in the cytoplasm and the nucleus whereas Trap1 regulates oxidative phosphorylation in mitochondria. Many of the associated proteins and cellular processes are relevant to cancer, and there is ample pharmacological and genetic evidence to support the idea that Hsp90a/βand Trap1 are required for tumorigenesis. However, a direct and comparative genetic test in a mouse cancer model has not been done. Here we report the effects of deleting the Hsp90a or Trap1 genes in a mouse model of breast cancer. Neither Hsp90a nor Trap1 are absolutely required for mammary tumor initiation, growth and metastasis induced by the polyoma middle T-antigen as oncogene. However, they do modulate growth and lung metastasis in vivo and cell proliferation, migration and invasion of isolated primary carcinoma cells in vitro. Without Hsp90a, tumor burden and metastasis are reduced, correlating with impaired proliferation, migration and invasion of cells in culture. Without Trap1, the appearance of tumors is initially delayed, and isolated cells are affected similarly to those without Hsp90a. Analysis of expression data of human breast cancers supports the conclusion that this is a valid mouse model highlighting the importance of these molecular chaperones.

TRAP1 regulates autophagy in lung cancer cells

“…It remains to be demonstrated whether the same occurs in lung cancer and whether modulation of autophagy plays a role. 50 In conclusion, our study provides evidence that modulation of TRAP1 expression influences the effect of autophagy on A549 cell viability providing new insights into possible therapeutic approaches regarding TRAP1-overexpressing tumours as the described results support the hypothesis that autophagy inhibition could constitute a good approach to induce tumour cell death with no strong implications to normal cells.…”

“…Furthermore, recent data demonstrated that cytosolic HSP90 and TRAP1 modulate growth and lung metastasis in vivo, although they do not play any role in the initiation of breast cancer. It remains to be demonstrated whether the same occurs in lung cancer and whether modulation of autophagy plays a role …”

Prognostic value of the mRNA expression of members of the HSP90 family in non‑small cell lung cancer

“…These two processes are frequently hijacked by cancer, leading to malignant cell motility, metastasis and extravasion ( 28 ). HSP90α modulates growth and lung metastasis by affecting the proliferation, migration and invasion of isolated primary carcinoma cells ( 29 ). One study indicated that the level of HSP90α in the plasma of patients with the advanced stages of malignant tumors was relatively high ( 30 ).…”

KCNQ1OT1 facilitates progression of non‐small‐cell lung carcinoma via modulating miRNA‐27b‐3p/HSP90AA1 axis

“…In a breast cancer mouse model, cytosolic HSP90α participated in tumor growth and lung metastasis in vivo. Furthermore, HSP90α −/− cells presented a significant reduction in cell migration (Vartholomaiou et al, ).…”