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.

三阴性乳腺癌 (TNBC) 是一种侵袭性疾病，远处转移后的 5 年相对生存率为 11%。为了在转移级联中存活下来，肿瘤细胞通过调节能量产生和上调生存途径来重塑其信号通路。AMP 活化蛋白激酶 (AMPK) 和 Akt 调节能量稳态和存活，然而，AMPK 和 Akt 同种型在 TNBC 细胞在肺定植过程中的个体或协同作用尚不清楚。本研究的目的是确定在循环癌细胞中靶向 Akt、AMPKα 或 Akt 和 AMPKα 同种型是否可以抑制 TNBC 肺定植。Akt1 或 Akt2 的瞬时沉默分别通过诱导细胞凋亡或抑制侵袭显着降低了肺的转移定植。重要的，使用 MK-2206 或 AZD5363 抑制剂对 Akt 活性的短暂药理学抑制并不能阻止 TNBC 细胞在肺组织中的定植。AMPKα1、AMPKα2 或 AMPKα1/2 的敲低对肺的转移性定植也没有影响。总之，这些研究结果表明，AMPK 同种型表达单独或与循环肿瘤细胞中的 Akt1 组合的瞬时降低不会协同降低 TNBC 转移性肺定植。我们的研究结果还提供证据表明 Akt1 和 Akt2 表达是一个瓶颈，可以挑战 TNBC 细胞对肺的定植。这些发现表明，单独或与循环肿瘤细胞中的 Akt1 组合的 AMPK 同种型表达的短暂降低不会协同降低 TNBC 转移性肺定植。我们的研究结果还提供证据表明 Akt1 和 Akt2 表达是一个瓶颈，可以挑战 TNBC 细胞对肺的定植。这些发现表明，单独或与循环肿瘤细胞中的 Akt1 组合的 AMPK 同种型表达的短暂降低不会协同降低 TNBC 转移性肺定植。我们的研究结果还提供证据表明 Akt1 和 Akt2 表达是一个瓶颈，可以挑战 TNBC 细胞对肺的定植。