Triple negative breast cancer (TNBC) is an aggressive disease with a 5-y relative survival rate of 11% after distant metastasis. To survive the metastatic cascade, tumor cells remodel their signaling pathways by regulating energy production and upregulating survival pathways. AMP-activated protein kinase (AMPK) and Akt regulate energy homeostasis and survival, however, the individual or synergistic role of AMPK and Akt isoforms during lung colonization by TNBC cells is unknown. The purpose of this study was to establish whether targeting Akt, AMPKα or both Akt and AMPKα isoforms in circulating cancer cells can suppress TNBC lung colonization. Transient silencing of Akt1 or Akt2 dramatically decreased metastatic colonization of lungs by inducing apoptosis or inhibiting invasion, respectively. Importantly, transient pharmacologic inhibition of Akt activity with MK-2206 or AZD5363 inhibitors did not prevent colonization of lung tissue by TNBC cells. Knockdown of AMPKα1, AMPKα2, or AMPKα1/2 also had no effect on metastatic colonization of lungs. Taken together, these findings demonstrate that transient decrease in AMPK isoforms expression alone or in combination with Akt1 in circulating tumor cells does not synergistically reduce TNBC metastatic lung colonization. Our results also provide evidence that Akt1 and Akt2 expression serve as a bottleneck that can challenge colonization of lungs by TNBC cells.
|Number of pages||10|
|Journal||Neoplasia (United States)|
|State||Published - Apr 2021|
Bibliographical noteFunding Information:
We acknowledge and thank the Research Communication Office of the Markey Cancer Center for assistance in preparing the figures and the manuscript. The Biostatistics and Bioinformatics Shared Resource Facility of the Markey Cancer Center conducted formal statistical analyses, and the Biospecimen Procurement & Translational Pathology Shared Resource Facility of the Markey Cancer Center acquired tissue sections (both supported by P30 CA177558).
This research was funded by National Institutes of Health grant R01 CA195573 (to BME), P30 CA177558, T32 CA160003 (for ZC), and Daphne's Legacy Breast Cancer Research Funds.
© 2021 The Authors
- Organ metastasis
- Triple negative breast cancer
ASJC Scopus subject areas
- Cancer Research