Biology and therapeutic potential of PI3K signaling in ER+/HER2-negative breast cancer

PI3K is a central node mediating growth factor receptor signaling. With its downstream effectors such as AKT and mTOR, and its crosstalk with the RAS/RAF/MEK/MAPK pathway, it plays a vital role in cancer cell proliferation, metabolism, and survival. Recent breast cancer (BC) molecular portraits delineate PI3K as the most frequently altered pathway, with recurrent PIK3CA mutations mostly found in the luminal subtypes of BC. The transcriptomic and proteomic signatures of PI3K pathway activation associate with reduced estrogen receptor α (ER) levels and activity, and with the luminal B subtype of BC that has a relatively poor outcome. However, oncogenic transforming PIK3CA mutations have been shown to predict a better outcome in ER+/HER2-negative BC treated with endocrine therapy. In this review, we summarize the recent findings in the cause-and-effect of PI3K pathway aberration and endocrine sensitivity, especially the crosstalk with the ER pathway. Potential therapeutic approaches based on these findings are also discussed.