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HER2 confers drug resistance of human breast cancer cells through activation of NRF2 by direct interaction.

ABSTRACT: Overexpression and/or activation of HER2 confers resistance of cancer cells to chemotherapeutic drugs. NRF2 also gives drug resistance of cancer cells through induction of detoxification and/or drug efflux proteins. Although several upstream effectors of NRF2 overlapped with the downstream molecules of HER2 pathway, no direct link between HER2 and NRF2 has ever been established. Here, we identified that co-expression of a constitutively active HER2 (HER2CA) and NRF2 increased the levels of NRF2 target proteins, HO-1 and MRP5. We also identified HER2CA activated the DNA-binding of NRF2 and the antioxidant response element (ARE)-mediated transcription in an NRF2-dependent manner. In addition, NRF2 and HER2CA cooperatively up-regulated the mRNA expression of various drug-resistant and detoxifying enzymes including GSTA2, GSTP1, CYP3A4, HO-1, MRP1, and MRP5. We also demonstrated that NRF2 binds to HER2 not only in transiently transfected HEK293T cells but also in HER2-amplified breast cancer cells. Functionally, overexpression of HER2CA gave resistance of MCF7 breast cancer cells to either paraquat or doxorubicin. Overexpression of dominant negative NRF2 (DN-NRF2) reduced the HER2CA-induced resistance of MCF7 cells to these agents. Taken together, these results suggest that active HER2 binds and regulates the NRF2-dependent transcriptional activation and induces drug resistance of cancer cells.

SUBMITTER: Kang HJ

PROVIDER: S-EPMC4252900 | biostudies-other | 2014 Dec

REPOSITORIES: biostudies-other

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HER2 confers drug resistance of human breast cancer cells through activation of NRF2 by direct interaction.

Kang Hyo Jin HJ Yi Yong Weon YW Hong Young Bin YB Kim Hee Jeong HJ Jang Young-Joo YJ Seong Yeon-Sun YS Bae Insoo I

Scientific reports 20141203

Overexpression and/or activation of HER2 confers resistance of cancer cells to chemotherapeutic drugs. NRF2 also gives drug resistance of cancer cells through induction of detoxification and/or drug efflux proteins. Although several upstream effectors of NRF2 overlapped with the downstream molecules of HER2 pathway, no direct link between HER2 and NRF2 has ever been established. Here, we identified that co-expression of a constitutively active HER2 (HER2CA) and NRF2 increased the levels of NRF2 ...[more]

PMID: 25467193

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Project description:BACKGROUND:HER2-positive breast cancer is usually associated to the more aggressive progression and the worse prognosis, but the mechanism underlying the innate resistance to HER2-targeted therapy remains elusive. The scaffold protein SH3-domain-binding glutamic acid-rich protein-like protein (SH3BGRL) is indicated as a tumor suppressor in some cancers, but it is highly expressed in breast cancers. Here we characterized the tumorigenic function of SH3BGRL in HER2-expressing breast cancer cells and the subsequent effect in HER2-targeted therapies. METHODS:The interaction of SH3BGRL to HER2 were characterized with various truncated SH3BGRL mutants by immunoprecipitation and molecule docking simulation. The physiological roles of SH3BGRL interacting with HER2 in tumor progression and therapy implication were characterized by gain and loss of function approaches in vitro and in vivo. Immunohistochemistry was used for detections of SH3BGRL and p-HER2 (Y1196) expressions in xenografted tumors and human breast cancer tissues. Clinical relevance of SH3BGRL expression with HER2 was validated with both breast patient sample and the public data analyses. RESULTS:Our results demonstrated that SH3BGRL directly binds with HER2 on cell membrane via its motifs ?1, ?2 helixes and ?3 sheet, which postpones HER2 internalization upon EGF stimulation. Consequently, the association between SH3BGRL and HER2 contributed to the prolonged HER2 phosphorylation at specific tyrosine sites, especially at Y1196, and their downstream signaling activation. The relevance between SH3BGRL expression and p-HER2 (Y1196) phosphorylation was validated in both xenografted tumors and the breast cancer patient tissues. Mechanistically, SH3BGRL promoted breast tumor cell proliferation and survival, while reduced the cell sensitivity to anti-tumor drugs, especially to the HER2-targeted drugs. In contrast, Silencing SH3BGRL or inhibiting its downstream signals efficiently induced apoptosis of breast tumor cells with HER2 and SH3BGRL doubly positive expression. Database analysis also highlighted that SH3BGRL is a poor prognostic marker, especially for HER2-positive breast cancers. CONCLUSIONS:Our results disclose SH3BGRL as a novel posttranslational modulator of HER2 hyperactivation, which can lead to the intrinsic resistance to HER2-targeted therapy. SH3BGRL would be a pivotal therapy target and a diagnostic marker to HER2-positve patients. Thus, targeting SH3BGRL or the downstream signaling could relieve the innate resistance to some HER2-tageted therapies for both HER2 and SH3BGRL-postive breast cancers.

Project description:The identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (HER2) has frequently been associated with both experimental and clinical endocrine therapy resistance, combined targeting of ER and HER2 has failed to improve overall survival in endocrine non-responsive disease. Herein, we questioned the role of fatty acid synthase (FASN), a lipogenic enzyme linked to HER2-driven breast cancer aggressiveness, in the development and maintenance of hormone-independent growth and resistance to anti-estrogens in ER/HER2-positive (ER+/HER2+) breast cancer. The stimulatory effects of estradiol on FASN gene promoter activity and protein expression were blunted by anti-estrogens in endocrine-responsive breast cancer cells. Conversely, an AKT/MAPK-related constitutive hyperactivation of FASN gene promoter activity was unaltered in response to estradiol in non-endocrine responsive ER+/HER2+ breast cancer cells, and could be further enhanced by tamoxifen. Pharmacological blockade with structurally and mechanistically unrelated FASN inhibitors fully impeded the strong stimulatory activity of tamoxifen on the soft-agar colony forming capacity-an in vitro metric of tumorigenicity-of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely prevented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antagonist properties against ER/HER2-positive xenograft tumors in mice. Functional cancer proteomic data from The Cancer Proteome Atlas (TCPA) revealed that the ER+/HER2+ subtype was the highest FASN protein expressor compared to basal-like, HER2-enriched, and ER+/HER2-negative breast cancer groups. FASN is a biological determinant of HER2-driven endocrine resistance in ER+ breast cancer. Next-generation, clinical-grade FASN inhibitors may be therapeutically relevant to countering resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas.

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HER2 confers drug resistance of human breast cancer cells through activation of NRF2 by direct interaction.

Publications

HER2 confers drug resistance of human breast cancer cells through activation of NRF2 by direct interaction.

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