PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D

Tumor cells develop resistance to a drug used to treat breast cancer through a chromatin remodeling mechanism. Chromatin state dictates drug response Drugs inhibiting the phosphoinositide-(3)-kinase (PI3K) signaling pathway are effective in a subset of breast cancer patients. Tumors become resistant to these drugs, however, and this transition is often accompanied by increased transcription of genes regulated by the estrogen receptor. A better understanding of the mechanism linking PI3K signaling and estrogen receptor activity could potentially suggest strategies to prevent drug resistance. Toska et al. found that PI3K inhibition activates a specific epigenetic regulator, the histone methyltransferase KMT2D. The protein modifications catalyzed by KMT2D create a more open chromatin state, which unleashes estrogen receptor–dependent transcription. Thus, combination therapies consisting of PI3K inhibitors and KMT2D inhibitors may be more effective than PI3K inhibitors alone. Science, this issue p. 1324 Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase α (PI3Kα), are frequently found in estrogen receptor (ER)–positive breast cancer. PI3Kα inhibitors, now in late-stage clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3Kα inhibition. We found that PI3Kα inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine 4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3Kα inhibition enhances KMT2D activity. These findings uncover a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer.