title: Targeting thyroid hormone receptor beta in triple-negative breast cancer.
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.
authors.affiliation: Lester and Sue Smith Breast Center, Dan L Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Guowei
authors.initials: G
authors.lastname: Gu
authors.forename: Luca
authors.initials: L
authors.lastname: Gelsomino
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Covington
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Beyer
authors.forename: John
authors.initials: J
authors.lastname: Wang
authors.forename: Yassine
authors.initials: Y
authors.lastname: Rechoum
authors.forename: Kenneth
authors.initials: K
authors.lastname: Huffman
authors.forename: Ryan
authors.initials: R
authors.lastname: Carstens
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
authors.forename: Suzanne A W
authors.initials: SA
authors.lastname: Fuqua
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology; D037042:Thyroid Hormone Receptors beta / Q000235:genetics* / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D037042:Thyroid Hormone Receptors beta; D000077143:Docetaxel; D004317:Doxorubicin
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