Abstract P6-04-19: Estrogen receptor β agonist S-Equol promotes letrozole sensitivity of endocrine therapy resistant breast cancer cells by upregulating FOXO3 expression

Abstract Female breast cancer has become the most commonly diagnosed cancer worldwide. As a tumor suppressor, estrogen receptor β (ERβ) is a potential target for breast cancer therapy. TAD1822-7 was evaluated for ERβ-mediated autophagy and cell death using cell proliferation assay, Annexin V/PI staining, immunofluorescence, western blotting and hypoxia cell models. TAD1822-7 upregulated ERβ causing cell death and induced mitochondrial dysfunction and autophagy companied with mitochondrial located ERβ. Enhanced levels of LC3-II and p62 indicated that TAD1822-7 blocked the late-stage autolysosome formation, leading to cell death. Mechanistically, TAD1822-7-induced cell death was mediated by PI3K/AKT signaling pathways. Moreover, TAD1822-7 modulated HIF functions and autophagy via the inhibition of HIF-1β in the context of hypoxia-induced autophagy. TAD1822-7 inhibited hypoxia-inducted autophagy and PI3K/AKT pathway. These findings provide new insight into the mechanism underlying the inhibitory effects of TAD1822-7 via ERβ-mediated pathways in breast cancer cells.

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Bisphenol AF as an Inducer of Estrogen Receptor β (ERβ): Evidence for Anti-estrogenic Effects at Higher Concentrations in Human Breast Cancer Cells

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.b17-00427 ◽

2017 ◽

Vol 40 (11) ◽

pp. 1909-1916 ◽

Cited By ~ 9

Author(s):

Hiroyuki Okazaki ◽

Shuso Takeda ◽

Kazuhiro Kakizoe ◽

Aya Taniguchi ◽

Miki Tokuyasu ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Estrogen Receptor Β ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Estrogenic Effects ◽

Bisphenol Af

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Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells

Cellular Physiology and Biochemistry ◽

10.1159/000495643 ◽

2018 ◽

Vol 51 (4) ◽

pp. 1518-1532 ◽

Cited By ~ 16

Author(s):

Pratima Basak ◽

Sumanta Chatterjee ◽

Vasudeva Bhat ◽

Alice Su ◽

Hyerang Jin ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

Endocrine Therapy ◽

Breast Cancer Cells ◽

Therapy Resistance ◽

Receptor Signaling ◽

Met Receptor ◽

Endocrine Therapy Resistance ◽

Organoid Cultures

Background/Aims: Blocking estrogen signaling with endocrine therapies (Tamoxifen or Fulverstrant) is an effective treatment for Estrogen Receptor-α positive (ER+) breast cancer tumours. Unfortunately, development of endocrine therapy resistance (ETR) is a frequent event resulting in disease relapse and decreased overall patient survival. The long noncoding RNA, H19, was previously shown to play a significant role in estrogen-induced proliferation of both normal and malignant ER+ breast epithelial cells. We hypothesized that H19 expression is also important for the proliferation and survival of ETR cells. Methods: Here we utilized established ETR cell models; the Tamoxifen (Tam)-resistant LCC2 and the Fulvestrant and Tam cross-resistant LCC9 cells. Gain and loss of H19 function were achieved through lentiviral transduction as well as pharmacological inhibitors of the Notch and c-Met receptor signaling pathways. The effects of altered H19 expression on cell viability and ETR were assessed using three-dimensional (3D) organoid cultures and 2D co-cultures with low passage tumour-associated fbroblasts (TAFs). Results: Here we report that treating ETR cells with Tam or Fulvestrant increases H19 expression and that it’s decreased expression overcomes resistance to Tam and Fulvestrant in these cells. Interestingly, H19 expression is regulated by Notch and HGF signaling in the ETR cells and pharmacological inhibitors of Notch and c-MET signaling together significantly reverse resistance to Tam and Fulvestrant in an H19-dependent manner in these cells. Lastly, we demonstrate that H19 regulates ERα expression at the transcript and protein levels in the ETR cells and that H19 protects ERα against Fulvestrant-mediated downregulation of ERα protein. We also observed that blocking Notch and the c-MET receptor signaling also overcomes Fulvestrant and Tam resistance in 3D organoid cultures by decreasing ERα and H19 expression in the ETR cells. Conclusion: In endocrine therapy resistant breast cancer cells Fulvestrant is ineffective in decreasing ERα levels. Our data suggest that in the ETR cells, H19 expression acts as an ER modulator and that its levels and subsequently ERα levels can be substantially decreased by blocking Notch and c-MET receptor signaling. Consequently, treating ETR cells with these pharmacological inhibitors helps overcome resistance to Fulvestrant and Tamoxifen.

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