Knockdown of AKT3 Activates HER2 and DDR Kinases in Bone-Seeking Breast Cancer Cells, Promotes Metastasis In Vivo and Attenuates the TGFβ/CTGF Axis

Hinz, Nico; Baranowsky, Anke; Horn, Michael P.; Kriegs, Malte; Sibbertsen, Freya; Smit, Daniel J; Clézardin, Philippe; Lange, Tobias; Schinke, Thorsten; Jücker, Manfred

doi:10.3390/cells10020430

Cited by 16 publications

(14 citation statements)

References 104 publications

(178 reference statements)

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“…Akt2 was also associated with worse clinical outcome and was considered a worthwhile target for breast cancer therapy [ 70 ]. Although Akt3 expression was believed to be restricted to neuronal cells, it is now known that it can also contribute to breast cancer, especially in TNBC [ 63 , 82 , 84 , 98 , 102 ].…”

Section: Discussionmentioning

confidence: 99%

“…Akt2 was reported to decrease [ 100 ], increase [ 71 , 73 , 89 ] or have no effect on cell proliferation and tumor growth [ 82 , 88 ]. Similarly, there are contrasting reports whether depletion of Akt3 increases migration, invasion, and bone metastasis [ 98 ], decreases cell proliferation and tumor growth [ 63 , 82 , 83 ], or has no effect on tumorigenesis and lung metastasis [ 100 ].…”

Section: Discussionmentioning

confidence: 99%

“…Akt1 E17K mutation in p53 null background inhibited cell migration and invasion in MCF-10A cells by decreasing ZEB1 which caused an increase in E-cadherin and reversal of EMT whereas Akt2 had opposite effect on E-cadherin [ 97 ]. While most of the studies have examined the involvement of Akt isoforms in lung metastases, Hinz et al showed that Akt3 but not Akt1 or Akt2 activity is elevated in a subline of MDA-MB-231 cells that metastasize to bone (MDA-MB-231 BO) and knockdown of Akt3 increased migration, invasion, and bone metastasis via activation of HER2 and discoidin domain receptor (DDR) kinases and downregulation of the TGFβ/CTGF (connective tissue growth factor) axis [ 98 ].…”

Section: Function Of Akt Isoformsmentioning

confidence: 99%

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Akt Isoforms: A Family Affair in Breast Cancer

Basu

Lambring

2021

Cancers

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Akt, also known as protein kinase B (PKB), belongs to the AGC family of protein kinases. It acts downstream of the phosphatidylinositol 3-kinase (PI3K) and regulates diverse cellular processes, including cell proliferation, cell survival, metabolism, tumor growth and metastasis. The PI3K/Akt signaling pathway is frequently deregulated in breast cancer and plays an important role in the development and progression of breast cancer. There are three closely related members in the Akt family, namely Akt1(PKBα), Akt2(PKBβ) and Akt3(PKBγ). Although Akt isoforms share similar structures, they exhibit redundant, distinct as well as opposite functions. While the Akt signaling pathway is an important target for cancer therapy, an understanding of the isoform-specific function of Akt is critical to effectively target this pathway. However, our perception regarding how Akt isoforms contribute to the genesis and progression of breast cancer changes as we gain new knowledge. The purpose of this review article is to analyze current literatures on distinct functions of Akt isoforms in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Function Of Akt Isoformsmentioning

confidence: 99%

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Akt Isoforms: A Family Affair in Breast Cancer

Basu

Lambring

2021

Cancers

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“…Furthermore, Li et al observed an increased metastasis to the lung in mice inoculated with breast cancer cells after treatment with a panAKT inhibitor [ 185 ]. Our laboratory recently showed an increased bone metastasis without the promotion of osteolysis after generating a knockdown of AKT3 in bone-metastatic breast cancer cells [ 186 ]. Thus, further research has to clarify the role of the various AKT isoforms in bone metastasis of various cancer entities to assess the possibility of an isoform-specific AKT inhibition and to rule out possible adverse effects associated with panAKT inhibition.…”

Section: Discussionmentioning

confidence: 99%

AKT in Bone Metastasis of Solid Tumors: A Comprehensive Review

Hinz

Jücker

2021

Cancers

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Solid tumors, such as breast cancer and prostate cancer, often form bone metastases in the course of the disease. Patients with bone metastases frequently develop complications, such as pathological fractures or hypercalcemia and exhibit a reduced life expectancy. Thus, it is of vital importance to improve the treatment of bone metastases. A possible approach is to target signaling pathways, such as the PI3K/AKT pathway, which is frequently dysregulated in solid tumors. Therefore, we sought to review the role of the serine/threonine kinase AKT in bone metastasis. In general, activation of AKT signaling was shown to be associated with the formation of bone metastases from solid tumors. More precisely, AKT gets activated in tumor cells by a plethora of bone-derived growth factors and cytokines. Subsequently, AKT promotes the bone-metastatic capacities of tumor cells through distinct signaling pathways and secretion of bone cell-stimulating factors. Within the crosstalk between tumor and bone cells, also known as the vicious cycle, the stimulation of osteoblasts and osteoclasts also causes activation of AKT in these cells. As a consequence, bone metastasis is reduced after experimental inhibition of AKT. In summary, AKT signaling could be a promising therapeutical approach for patients with bone metastases of solid tumors.

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“…Similar to Akt1 inhibition, Akt3 deficiency also promotes breast cancer cells migration, invasion and metastasis due to upregulation of S100A4 and increased activation of HER2 and discoidin domain receptor tyrosine kinase 1/2 [ 179 , 180 ]. In the murine breast cancer cell line PyMT, the cell–cell adhesion molecule N-cadherin downregulates Akt3 and then reduces cell motility [ 181 ].…”

Section: The Targets and Functions Of Aktmentioning

confidence: 99%

Targeting Akt in cancer for precision therapy

et al. 2021

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Biomarkers-guided precision therapeutics has revolutionized the clinical development and administration of molecular-targeted anticancer agents. Tailored precision cancer therapy exhibits better response rate compared to unselective treatment. Protein kinases have critical roles in cell signaling, metabolism, proliferation, survival and migration. Aberrant activation of protein kinases is critical for tumor growth and progression. Hence, protein kinases are key targets for molecular targeted cancer therapy. The serine/threonine kinase Akt is frequently activated in various types of cancer. Activation of Akt promotes tumor progression and drug resistance. Since the first Akt inhibitor was reported in 2000, many Akt inhibitors have been developed and evaluated in either early or late stage of clinical trials, which take advantage of liquid biopsy and genomic or molecular profiling to realize personalized cancer therapy. Two inhibitors, capivasertib and ipatasertib, are being tested in phase III clinical trials for cancer therapy. Here, we highlight recent progress of Akt signaling pathway, review the up-to-date data from clinical studies of Akt inhibitors and discuss the potential biomarkers that may help personalized treatment of cancer with Akt inhibitors. In addition, we also discuss how Akt may confer the vulnerability of cancer cells to some kinds of anticancer agents.

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Knockdown of AKT3 Activates HER2 and DDR Kinases in Bone-Seeking Breast Cancer Cells, Promotes Metastasis In Vivo and Attenuates the TGFβ/CTGF Axis

Cited by 16 publications

References 104 publications

Akt Isoforms: A Family Affair in Breast Cancer

Akt Isoforms: A Family Affair in Breast Cancer

AKT in Bone Metastasis of Solid Tumors: A Comprehensive Review

Targeting Akt in cancer for precision therapy

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