Cytoplasmic Cyclin E Mediates Resistance to Aromatase Inhibitors in Breast Cancer

Abstract

Purpose Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E (low molecular weight forms [LMW-E]) have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect. Experimental Design LMW-E was examined in breast cancer specimen from 58 patients enrolled in the American College of Surgeons Oncology Group Z1031, a neoadjuvant AI clinical trial. The mechanisms of LMW-E mediated resistance to AI were evaluated in vitro and in vivo using an inducible model system of cyclin E (full-length and LMW-E) in aromatase-overexpressing MCF7 cells. Results Breast cancer recurrence-free interval was significantly worst in LMW-E positive patients who received AI neoadjuvant therapy. Upon LMW-E induction, MCF7 xenografts were unresponsive to letrozole in vivo, resulting in increased tumor volume after treatment with AIs. LMW-E expression overcame cell cycle inhibition by AIs in a CDK2/Rb-dependent manner and inhibition of CDK2 by dinaciclib reversed LMW-E-mediated resistance, while treatment with palbociclib, a CDK4/6 inhibitor, did not. Conclusion Collectively, these findings suggest that cell cycle deregulation by LMW-E mediates resistance to AIs and a combination of CDK2 inhibitors and AIs may be an effective treatment in patients with HR-positive tumors that express LMW-E.

α-bisabolol enhances radiotherapy-induced apoptosis in endometrial cancer cells by reducing the effect of XIAP on inhibiting caspase-3

“…Cyclin E is a key protein to regulate the transition of cells from G 1 to S phase. It contributes to unrestricted proliferation of cancer cells via controlling RB pathway [13][14][15]. Thus, the deregulation of cyclin E usually is linked to various malignancies, for example, lung, breast, ovarian or endometrial cancer [14,[16][17][18].…”

Molecular targets of curcumin in breast cancer (Review)

“…The drug achieves this arrest by stimulating the proteosomal degradation of cyclin E and upregulating CDK inhibitors, p53, p21 and p27; the addition of specific proteosomal inhibitors suppresses these effects of curcumin (48). Cyclin E is a nuclear protein that serves an important role in G 1 /S progression by interacting with its catalytic partner, CDK2, and by interacting with the retinoblastoma (Rb) protein (49,50). It appears likely that the anti-proliferative effects of curcumin are due to proteasome-mediated downregulation of cyclin E and upregulation of CDK inhibitors (51).…”

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

“…Generally, AIs and fulvestrant are used to follow or replace when patients are resistant to tamoxifen [71,72]. However, resistance to AIs and fulvestrant eventually occurs [73][74][75].…”