ABSTRACT
Although it is established that fatty acid (FA) synthesis supports anabolic growth in cancer, the role of exogenous FA uptake remains elusive. Here we show that, during acquisition of resistance to HER2 inhibition, metabolic rewiring of breast cancer cells favors reliance on exogenous FA uptake over de novo FA synthesis. Through cDNA microarray analysis, we identify the FA transporter CD36 as a critical gene upregulated in cells with acquired resistance to the HER2 inhibitor lapatinib. Accordingly, resistant cells exhibit increased exogenous FA uptake and metabolic plasticity. Genetic or pharmacological inhibition of CD36 suppresses the growth of lapatinib-resistant but not lapatinib-sensitive cells in vitro and in vivo. Deletion of Cd36 in mammary tissues of MMTV-neu mice significantly attenuates tumorigenesis. In breast cancer patients, CD36 expression increases following anti-HER2 therapy, which correlates with a poor prognosis. Our results define CD36-mediated metabolic rewiring as an essential survival mechanism in HER2-positive breast cancer.
Subject(s)
Breast Neoplasms/metabolism , CD36 Antigens/metabolism , Drug Resistance, Neoplasm , Fatty Acids/metabolism , Receptor, ErbB-2/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , CD36 Antigens/genetics , Cell Line, Tumor , Female , Humans , Lapatinib/pharmacology , Lapatinib/therapeutic use , Mice , Mice, Inbred NOD , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic useABSTRACT
The ubiquitin E3 ligase MDM2 is best known for its ability to suppress the tumor suppressor p53. However, MDM2 also targets other proteins for proteasomal degradation and accumulating evidence strongly suggests p53-independent roles of MDM2 in cancer. We previously reported that MDM2 promotes degradation of another ubiquitin E3 ligase HUWE1 by ubiquitination, particularly, which confers HER2+ breast cancer cells resistance to the HER2 inhibitor lapatinib. However, it remains unclear whether such a mechanism can operate in other cell types, independently of HER2 inhibitors. Moreover, in vivo evidence that supports HUWE1 degradation by MDM2 is missing. In the current study, we performed immunohistochemistry (IHC) to analyze expression levels of MDM2 and HUWE1 in normal organs, two breast cancer cohorts (A, n = 137 and B, n = 27), and a liposarcoma cohort (n = 45). Our results show that HUWE1 is ubiquitously expressed in healthy organs, where the oncoprotein MDM2 is undetectable. Likewise, in the majority of breast cancers regardless of their subtypes, MDM2 is below detectable levels, while HUWE1 is highly expressed. In contrast, in a subset of liposarcoma that is characterized by MDM2 overexpression, only 40% of these showed detectable HUWE1 protein. Importantly, despite the inverse association between MDM2 and HUWE1 protein levels, gene expression analysis in independent datasets revealed no such correlation at the mRNA level. Our results demonstrate the first in vivo evidence to support the hypothesis of MDM2-mediated HUWE1 degradation, which may help to understand the regulation of HUWE1 as well as p53-independent roles of MDM2.
ABSTRACT
Approximately 25% of breast cancers overexpress and depend on the receptor tyrosine kinase ERBB2, one of 4 ERBB family members. Targeted therapies directed against ERBB2 have been developed and used clinically, but many patients continue to develop resistance to such therapies. Although much effort has been focused on elucidating the mechanisms of acquired resistance to ERBB2-targeted therapies, the involvement of ERBB4 remains elusive and controversial. We demonstrate that genetic ablation of ERBB4, but not ERBB1-3, led to apoptosis in lapatinib-resistant cells, suggesting that the efficacy of pan-ERBB inhibitors was, at least in part, mediated by the inhibition of ERBB4. Moreover, ERBB4 was upregulated at the protein level in ERBB2+ breast cancer cell lines selected for acquired lapatinib resistance in vitro and in MMTV-Neu mice following prolonged lapatinib treatment. Knockdown of ERBB4 caused a decrease in AKT phosphorylation in resistant cells but not in sensitive cells, suggesting that ERBB4 activated the PI3K/AKT pathway in lapatinib-resistant cells. Importantly, ERBB4 knockdown triggered apoptosis not only in lapatinib-resistant cells but also in trastuzumab-resistant cells. Our results suggest that although ERBB4 is dispensable for naïve ERBB2+ breast cancer cells, it may play a key role in the survival of ERBB2+ cancer cells after they develop resistance to ERBB2 inhibitors, lapatinib and trastuzumab.
