# WBP2 Attenuates Metformin Response in HER2-Positive Breast Cancer Cells by Repressing AMPK Activation and Inducing a Lower AMP:ATP Ratio State Through Enhanced ATP Production

## TL;DR

WBP2 reduces the effectiveness of metformin in HER2-positive breast cancer by altering energy metabolism and AMPK activation.

## Contribution

WBP2 is identified as a novel regulator of metformin response in HER2+ breast cancer through its impact on AMPK and ATP production.

## Key findings

- WBP2 inhibits metformin-induced AMPK activation in HER2+ breast cancer cells.
- WBP2 promotes glycolytic capacity and mitochondrial respiration, lowering the AMP:ATP ratio.
- Clinical analysis supports a negative correlation between WBP2 and activated AMPK in HER2+ breast cancer.

## Abstract

What are the main findings?
WBP2 inhibits the metformin response of HER2+ breast cancer cells.WBP2 represses metformin-induced AMPK activation while concomitantly decreasing AMP:ATP ratio through promoting glycolytic capacity and mitochondria respiration.

WBP2 inhibits the metformin response of HER2+ breast cancer cells.

WBP2 represses metformin-induced AMPK activation while concomitantly decreasing AMP:ATP ratio through promoting glycolytic capacity and mitochondria respiration.

What are the implications of the main findings?
WBP2 is a potential biomarker for predicting response and facilitates repurposing of metformin for cancer therapy.

WBP2 is a potential biomarker for predicting response and facilitates repurposing of metformin for cancer therapy.

Metformin is an antidiabetic drug that has been tested widely as an anti-cancer agent. However, data from clinical trials have been mixed. Evidence for metformin’s efficacy in HER2+ breast cancer exists. Hence, we evaluated whether WBP2, a HER2-coamplified gene, can regulate the response of HER2+ breast cancer to metformin. Identification of biomarkers for predicting metformin response has implications in repurposing metformin for precision oncology. The effect of WBP2 on breast cancer response to metformin was studied using in vitro and mouse models. The mechanism of WBP2 on metformin-induced AMPK activation was elucidated, and its co-expression with p-AMPK was examined in clinical specimens using IHC. RNA-seq analyses were performed to elucidate WBP2’s mechanism in energy metabolism. WBP2 inhibited the metformin response of HER2+ breast cancer in vitro and in vivo. These effects were concomitant with WBP2-mediated repression of metformin-induced AMPK activation and mTOR inhibition in HER2+ breast cancer cells, a lower AMP:ATP ratio state, and enhanced glycolytic capacity and mitochondria respiration. Analysis of HER2-positive breast cancer samples supports the negative correlation between WBP2 expression and activated AMPK observed in vitro. RNA-seq analysis revealed the potential mechanism of WBP2 in regulating ATP production processes and preferential effect of WBP2 on metformin response in HER2+ breast cancer. This study reported a novel role of WBP2 in cancer metabolism and energetics that contributes new insights into the molecular etiology of cancer. WBP2 may be a biomarker for patient stratification, paving the way towards repurposing metformin for precision oncology.