Studies in three mouse models of breast cancer identified profound discrepancies between cell-autonomous and systemic Akt1- or Akt2-inducible deletion on breast cancer tumorigenesis and metastasis. Although systemic Akt1 deletion inhibits metastasis, cell-autonomous Akt1 deletion does not. Single-cell mRNA sequencing revealed that systemic Akt1 deletion maintains the pro-metastatic cluster within primary tumors but ablates pro-metastatic neutrophils. Systemic Akt1 deletion inhibits metastasis by impairing survival and mobilization of tumor-associated neutrophils. Importantly, either systemic or neutrophil-specific Akt1 deletion is sufficient to inhibit metastasis of Akt-proficient tumors. Thus, Akt1-specific inhibition could be therapeutic for breast cancer metastasis regardless of primary tumor origin. Systemic Akt2 deletion does not inhibit and exacerbates mammary tumorigenesis and metastasis, but cell-autonomous Akt2 deletion prevents breast cancer tumorigenesis by ErbB2. Elevated circulating insulin level induced by Akt2 systemic deletion hyperactivates tumor Akt, exacerbating ErbB2-mediated tumorigenesis, curbed by pharmacological reduction of the elevated insulin.

对三种乳腺癌小鼠模型的研究确定了细胞自主性和全身性 Akt1 或 Akt2 诱导性缺失对乳腺癌肿瘤发生和转移的巨大差异。虽然全身性 Akt1 缺失抑制转移，但细胞自主 Akt1 缺失不会。单细胞 mRNA 测序显示，系统性 Akt1 缺失维持原发肿瘤内的促转移簇，但会消融促转移的中性粒细胞。全身性 Akt1 缺失通过损害肿瘤相关中性粒细胞的存活和动员来抑制转移。重要的是，全身性或中性粒细胞特异性 Akt1 缺失足以抑制 Akt 熟练肿瘤的转移。因此，无论原发肿瘤起源如何，Akt1 特异性抑制都可以治疗乳腺癌转移。系统性 Akt2 缺失不会抑制和加剧乳腺肿瘤的发生和转移，但细胞自主的 Akt2 缺失可防止 ErbB2 引起乳腺癌的发生。由 Akt2 系统性缺失诱导的循环胰岛素水平升高会过度激活肿瘤 Akt，加剧 ErbB2 介导的肿瘤发生，而升高的胰岛素的药理学降低可抑制这种情况。