Autoantibodies Specific to ERα are Involved in Tamoxifen Resistance in Hormone Receptor Positive Breast Cancer.

Angela Maselli,Elena Ortona,Rossella Puglisi,Daniele Macchia,Elisabetta Iessi,Stefania Parlato,Marina Pierdominici,Patrizia Vici,Carla Raggi,Francesca Cirulli,Giada Pontecorvi,Laura Pizzuti,Massimo Spada,Alessandra Carè,Maddalena Barba,Maria Teresa Pagano,Paola Matarrese,Lucia Gabriele

doi:10.3390/cells8070750

Angela Maselli, Elena Ortona + Show 16 more

Open Access

https://doi.org/10.3390/cells8070750

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Abstract

Tamoxifen resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. The mechanisms of tamoxifen resistance are not fully understood although several underlying molecular events have been suggested. Recently, we identified autoantibodies reacting with membrane-associated ERα (anti-ERα Abs) in sera of breast cancer patients, able to promote tumor growth. Here, we investigated whether anti-ERα Abs purified from sera of ER-positive breast cancer patients could contribute to tamoxifen resistance. Anti-ERα Abs inhibited tamoxifen-mediated effects on cell cycle and proliferation in MCF-7 cells. Moreover, anti-ERα Abs hampered the tamoxifen-mediated reduction of tumor growth in SCID mice xenografted with breast tumor. Notably, simvastatin-mediated disaggregation of lipid rafts, where membrane-associated ERα is embedded, restored tamoxifen sensitivity, preventing anti-ERα Abs effects. In conclusion, detection of serum anti-ERα Abs may help predict tamoxifen resistance and concur to appropriately inform therapeutic decisions concerning hormone therapy in ER-positive breast cancer patients.

Highlights

Estrogens are known to have a major role in the onset and progression of breast cancer and almost70% of breast tumors express estrogen receptor α (ERα) [1,2,3]
The Anti-Proliferative Effects of Tamoxifen is Inhibited by Anti-ERα Abs
We have previously observed that human anti-ERα Abs were able to act as mERα agonists inducing in vitro in breast cancer MCF-7 cell line the following effects: (i) rapid activation of extracellular signal-regulated kinase (ERK); and (ii) increase of cell proliferation [13]

Summary

Introduction

Estrogens are known to have a major role in the onset and progression of breast cancer and almost. 70% of breast tumors express estrogen receptor α (ERα) [1,2,3]. ERα functions as a ligand dependent transcription factor that directly binds to specific estrogen responsive elements, regulating the transcription of estrogen-sensitive genes [4]. The selective ER modulator (SERM) tamoxifen (TAM), which binds to and neutralizes ERα, is one of the treatments of choice for ER-positive breast cancer patients for all stages of the disease in both pre- and post-menopausal women [1,7]. A large proportion of ER-positive patients show intrinsic or acquired drug resistance and relapse during or after endocrine therapy [8,9]. Several molecular mechanisms underlying TAM resistance have been suggested, including ERα

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