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Physiological expression of PI3K H1047R mutation reveals its anti-metastatic potential in ErbB2-driven breast cancer

Abstract

p110α is a catalytic subunit of phosphoinositide 3-kinase (PI3K), a major downstream effector of receptor tyrosine kinase ErbB2, that is amplified and overexpressed in 20–30% of breast cancers, 40% of which have an activating mutation in p110α. Despite the high frequency of PIK3CA gain-of-function mutations, their prognostic value is controversial. Here, we employ a knock-in transgenic strategy to restrict the expression of an activated form of ErbB2 and p110α kinase domain mutation (p110αHR) in the mammary epithelium. Physiological levels of transgene expression under the control of their endogenous promoters did not result in a major synergistic effect. However, tumors arising in ErbB2/p110αHR bi-genic strain metastasized to the lung with significantly reduced capacity compared to tumors expressing ErbB2 alone. The reduced metastasis was further associated with retention of the myoepithelial layer reminiscent of ductal carcinoma in situ (DCIS), a non-invasive stage of human breast cancer. Molecular and biochemical analyses revealed that these poorly metastatic tumors exhibited a significant decrease in phospho-myosin light chain 2 (MLC2) associated with cellular contractility and migration. Examination of human samples for MLC2 activity revealed a progressive increase in cellular contractility between non-invasive DCIS and invasive ductal carcinoma. Collectively, these data argue that p110αHR mutation attenuates metastatic behavior in the context of ErbB2-driven breast cancer.

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Fig. 1: Physiological expression of p110αHR decreases ErbB2 protein levels and protects from lung metastasis.
Fig. 2: Tumors expressing p110αHR maintain DCIS pathology and strong cell-cell junctions.
Fig. 3: The p110αHR mutation impairs MLC2 activity which is important to cell contractility and motility.
Fig. 4: Progressive increase in MLC2 activity is correlated with breast cancer invasive progression.

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Acknowledgements

This work was supported by a Canada Research Councils Chair in Molecular Oncology (950-2310-33), and a Foundation award from the Canadian Institutes of Health Research (CIHR-FDN-148373) (all to W.J.M.).

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Conceptualization: AMS, TR, WJM; investigation: AMS, TB, VS, DM; analysis: AMS, TB, RDC; resources: WAP; writing: AMS, TB, WJM; review and editing: AMS, TB, WAP, WJM; visualization: AMS, TB; funding acquisition: WJM; supervision: WJM.

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Correspondence to William J. Muller.

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Simond, A.M., Bui, T., Zuo, D. et al. Physiological expression of PI3K H1047R mutation reveals its anti-metastatic potential in ErbB2-driven breast cancer. Oncogene 41, 3445–3451 (2022). https://doi.org/10.1038/s41388-022-02323-9

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