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

Abstract

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.

Keywords: Breast cancer; Crosstalk; Estrogen receptor; Feedback loop; PI3K; PIK3CA mutation.

Figure 1

(Adapted from Ref ). Proteomic and transcriptomic signatures of PI3K signaling are associated with lower ER and PR levels in ER+ BC and with the luminal B subtype. A. Heat map of ER+ BC by their PI3K proteomic signature score, computed from the sum of listed phosphoprotein levels minus the level of the negative regulator of the pathway, PTEN, along with corresponding levels of ER and PR, and intrinsic molecular subtype association (luminal A vs. luminal B). Tumors are ranked from low to high PI3K activity score. B. Heat map of ER+ BC by the PI3K transcriptomic signature score. The CMap dataset was used to compute the PI3K transcriptomic score in each tumor. Tumors are ranked from low to high PI3K pathway score, based on the similarity of their gene expression pattern to the PI3K gene signature. *P<0.001, Spearman’s correlation (ER/PR association) and t-test (luminal subtype association).

Figure 2

Schematic overview of multiple feedback loops in the PI3K pathway. As described in this review, activation of PI3K/AKT signaling is involved in at least three negative feedback loops. (i) Activated mTORC1/S6K1 phosphorylates IRS1, leading to its degradation and subsequently to attenuated IRS1-mediated PI3K and RAS/MEK/MAPK activation. (ii) Activated S6K1 phosphorylates and suppresses mTORC2 activity, resulting in decreased phosphorylation levels of AKT at serine 473, which fails to enhance the catalytic activity of AKT already phosphorylated at threonine 308 by PDK1. (iii) Activated AKT phosphorylates and inactivates FoxO transcription factors resulting in their nuclear exclusion, thus preventing them from transcriptional activation of RTKs such as HER3, IGF1-R, and InsR, which in turn attenuates the input upstream signaling.