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Targeting thyroid hormone receptor beta in triple-negative breast cancer

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Abstract

The purpose of this study was to discover novel nuclear receptor targets in triple-negative breast cancer. Expression microarray, Western blot, qRT-PCR analyses, MTT growth assay, soft agar anchorage-independent growth assay, TRE reporter transactivation assay, and statistical analysis were performed in this study. We performed microarray analysis using 227 triple-negative breast tumors, and clustered the tumors into five groups according to their nuclear receptor expression. Thyroid hormone receptor beta (TRβ) was one of the most differentially expressed nuclear receptors in group 5 compared to other groups. TRβ low expressing patients were associated with poor outcome. We evaluated the role of TRβ in triple-negative breast cancer cell lines representing group 5 tumors. Knockdown of TRβ increased soft agar colony and reduced sensitivity to docetaxel and doxorubicin treatment. Docetaxel or doxorubicin long-term cultured cell lines also expressed decreased TRβ protein. Microarray analysis revealed cAMP/PKA signaling was the only KEGG pathways upregulated in TRβ knockdown cells. Inhibitors of cAMP or PKA, in combination with doxorubicin further enhanced cell apoptosis and restored sensitivity to chemotherapy. TRβ-specific agonists enhanced TRβ expression, and further sensitized cells to both docetaxel and doxorubicin. Sensitization was mediated by increased apoptosis with elevated cleaved PARP and caspase 3. TRβ represents a novel nuclear receptor target in triple-negative breast cancer; low TRβ levels were associated with enhanced resistance to both docetaxel and doxorubicin treatment. TRβ-specific agonists enhance chemosensitivity to these two agents. Mechanistically enhanced cAMP/PKA signaling was associated with TRβ’s effects on response to chemotherapy.

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Abbreviations

AR:

Androgen receptor

CIS or C:

Cisplatin

DOC or T:

Docetaxel

DOX or D:

Doxorubicin

ERα:

Estrogen receptor alpha

EV:

Empty vector

KD:

Knockdown

LAR:

Luminal AR

NRs:

Nuclear receptors

PAM:

Prediction analysis of microarrays

TRβ:

Thyroid hormone receptor beta

TNBC:

Triple-negative breast cancer

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Acknowledgments

The authors would like to thank Dr. Paul Webb from Houston Methodist Research Institute for kindly providing us the TRβ agonists GC-1 and KB-141. We would like to thank Dr. Meng Gao for generating the heat map of Fig. 1a. This work was supported by NIH/NCI R01-CA72038, CPRIT RP120732-P2, and Susan G Komen for the Cure PG12221410.

Conflict of interest

Authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Lester and Sue Smith Breast Center, Dan L Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Guowei Gu, Luca Gelsomino, Kyle R. Covington, Amanda R. Beyer, John Wang, Yassine Rechoum & Suzanne A. W. Fuqua

  2. Southwestern Medical Center, University of Texas, Dallas, TX, USA

    Kenneth Huffman & Ryan Carstens

  3. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Arcavacata di Rende, CS, Italy

    Sebastiano Andò

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  1. Guowei Gu
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  2. Luca Gelsomino
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Correspondence to Suzanne A. W. Fuqua.

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10549_2015_3354_MOESM1_ESM.pptx

Sup. Figure 1.Hierarchical clustering was performed using 41 NR’s to classify227 ER-negative tumors. Contributing receptors were scored using prediction analysis of microarrays [33] across clustered groups; Sup. Figure 2.MDA-MB-453 cells with an inducible TRβ vector were treated with three doses of doxycycline for 48 h,and TRβ expression was evaluated using Western blot. GAPDH was used as positive control. Cells were also treated with doxycycline in combination with DOC or DOX for 6 days and then MTT assays were performed to measure cell viability. Results are expressed as fold change ± SD relative to vehicle control (C) cells.* p < 0.05, **p < 0.01; Sup. Figure 3.DAVID analysis was used to identify significant differential expression of the chemokine signaling pathway. Altered genes included chemokines (CCL2, CX3CL1), Gαi (GNAI1), AC (ADCY2), and PKA (PRKACB) and are denoted with red stars; Sup. Figure 4. HCC2185 cells were treated with H89 or Dox alone or in combination for 4 days and protein expression of TRβ, pPKA, PKA, cleaved caspase 3 and caspase 3 expression evaluated by Western blot analysis; GAPDH was used as a loading control; Sup. Figure 5HCC202 EV or SH cells were transfected with TRE reporterand beta galactosidasefor 24 h, and then treated for an additional 24 h with T3, GC-1, or KB141.Cells were then evaluated for TR transcriptional activity. Results are expressed as fold change ± SD relative to vehicle treated cells. * p < 0.05, **p < 0.01, *** p < 0.001, NS = No Significant; Sup. Figure. 6.A.HCC202 cells were treated with GC-1, KB-141, or vehicle for 5 days and TRβ expression measured using Western blot analysis. GAPDH was used as control. B. HCC202 cells were treated with DOXalone and in combination with GC-1 or KB-141 for 9 days and then MTT assays were formed. Results are expressed as fold change ± SD relative to vehicle treated cells (*** p < 0.001) C. HCC202 cells were treated with DOX or GC-1 alone or in combination for 6 days, and MTT growth assays were performed. * p < 0.05. Supplementary material 1 (PPTX 429 kb)

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Gu, G., Gelsomino, L., Covington, K.R. et al. Targeting thyroid hormone receptor beta in triple-negative breast cancer. Breast Cancer Res Treat 150, 535–545 (2015). https://doi.org/10.1007/s10549-015-3354-y

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