ER and PI3K independently modulate endocrine resistance in ER-positive breast cancer

Abstract

Endocrine therapy-resistant estrogen receptor-positive (ER(+)) breast cancer is the most common cause of breast cancer death. Miller and colleagues demonstrate that ligand-independent ER activity promotes the growth of breast cancer cells through CDK4/E2F. As an independent event, the phosphatidylinositol 3-kinase (PI3K) pathway is also upregulated in endocrine therapy-resistant cells. Promising preclinical evidence by several groups for the combination of an inhibitor of ligand-independent ER, fulvestrant, with PI3K inhibition, has led to the activation of trials evaluating this concept.

Figure 1

By targeting both the survival and proliferation pathways, there is a synergistic effect on tumor cell death. A. Fulvestrant targets ER for proteosomal degradation which down regulates E2F transcription. B. Inhibition of CDK4 by PD-0332991 inhibits phosphorylation of Rb which in turn prevents the release of E2F from Rb repression. Both Fulvestrant and PD-0332991 accomplish the goal of down regulating E2F and down regulating the proliferation signal. C. Inhibition of PI3K by BMK120 decreases the pro-survial signal from PI3K.