Downregulation of GLUT4 contributes to effective intervention of estrogen receptor-negative/HER2-overexpressing early stage breast disease progression by lapatinib.
Tamoxifen and aromatase inhibitors (AIs) have shown efficacy in prevention of estrogen receptor-positive (ER+) breast cancer; however, there exists no proven prevention strategy for estrogen receptor-negative (ER-) breast cancer. Up to 40% of ER- breast cancers have human epidermal growth factor receptor 2 overexpression (HER2+), suggesting HER2 signaling might be a good target for chemoprevention for certain ER- breast cancers. Here, we tested the feasibility of the HER2-targeting agent lapatinib in prevention and/or early intervention of an ER-/HER2+ early-stage breast disease model. We found that lapatinib treatment forestalled the progression of atypical ductal hyperplasia (ADH)-like acini to ductal carcinoma in situ (DCIS)-like acini in ER-/HER2+ human mammary epithelial cells (HMECs) in 3D culture. Mechanistically, we found that inhibition of HER2/Akt signaling by lapatinib led to downregulation of GLUT4 and a reduced glucose uptake in HER2-overexpressing cells, resulting in decreased proliferation and increased apoptosis of these cells in 3D culture. Additionally, our data suggest that HER2-driven glycolytic metabolic dysregulation in ER-/HER2+ HMECs might promote early-stage breast disease progression, which can be reversed by lapatinib treatment. Furthermore, low-dose lapatinib treatment, starting at the early stages of mammary grand transformation in the MMTV-neu* mouse model, significantly delayed mammary tumor initiation and progression, extended tumor-free survival, which corresponded to effective inhibition of HER2/Akt signaling and downregulation of GLUT4 in vivo. Taken together, our results indicate that lapatinib, through its inhibition of key signaling pathways and tumor-promoting metabolic events, is a promising agent for the prevention/early intervention of ER-/HER2+ breast cancer progression.
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer CenterHouston, TX 77030, USA; Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at HoustonHouston, TX 77030, USA.
Sunil
S
Acharya
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center Houston, TX 77030, USA.
Jia
J
Xu
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center Houston, TX 77030, USA.
Xiao
X
Wang
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center Houston, TX 77030, USA.
Shalini
S
Jain
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center Houston, TX 77030, USA.
Hai
H
Wang
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center Houston, TX 77030, USA.
Qingling
Q
Zhang
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer CenterHouston, TX 77030, USA; Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at HoustonHouston, TX 77030, USA.
Chia-Chi
CC
Chang
CPRIT-CURE Summer Program, The University of Texas M. D. Anderson Cancer Center Houston, TX 77030, USA.
Joseph
J
Bower
Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center Houston, TX 77030, USA.
Banu
B
Arun
Department of Population Sciences City of Hope, Duarte, CA 91010, USA.
Victoria
V
Seewaldt
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer CenterHouston, TX 77030, USA; Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at HoustonHouston, TX 77030, USA.
Dihua
D
Yu
ER-/HER2+ breast cancer; GLUT4; Lapatinib; cancer prevention