Abstract
Abstract Background: The treatment of estrogen receptor (ER)-negative breast cancer (BC) is a major clinical problem due to the lack of useful therapeutic targets. Nuclear receptors (NRs) are potential targets in these patients because they regulate global transcriptional events and many already have agonists/antagonists available. Material and Methods: We used microarray analysis of 227 ER-negative tumors to identify NR targets, and performed hierarchical clustering using 41 NRs. Expressed receptors were scored using prediction analysis of microarrays (PAM) across clustered groups. Cell lines were matched to subtypes using previously described data (Neve et al. 2006). Candidate gene expression levels were confirmed by qRT-PCR using TaqMan probes. pGIPZ lentiviral vectors encoding shRNA were used to knockdownselected candidates. MTT and soft agar assays were used to measure chemosensitivity and growth following treatment with Docetaxel (Doc), Doxorubicin (Dox), or Cisplatin (Cis). Statistical analysis was performed using Red-R. Results: The 41 NRs clustered tumors into 5 groups. For each group we selected genes representing the highest ranked discriminators, and examined their effects in cell lines matching each groups' gene signature. Thyroid hormone receptor b (THRβ) was selected from group V. The expression levels of this receptor were confirmed by qRT-PCR and Western blot analysis. Knockdown of THRβ in ER-negative HCC2185 cells rendered cells more resistant to all chemotherapeutics by using MTT assay. Similar results were confirmed in ER-negative MDA-MB-453 and HCC202 cells. Knockdown of THRβ enhanced colony forming potential in anchorage-independent soft agar assays in MDA-MB-453 and HCC202 cells. Statistical analysis using clinical data from Sabatier et al. (BCRT 2011) showed that patients with low THRb have a worse clinical outcome. In order to translate these findings into the clinic, we treated cells with a specific THRβ agonists, GC-1 and KB-141. GC-1 inhibited cell growth in growth assays, and synergistic effects were observed when cells were treated with GC-1 and Docetaxel in combination. Re-expression of ERα protein was observed in ER-nagative cells lines after treatment with GC-1 and KB141, suggesting that modulation of THRβ may also extend hormonal therapy to this hormonally insensitive group of patients. Conclusion: Clinical targeting of NRs in ER-negative BCs is a novel strategy since receptors can be specifically targeted with ligands. Our data suggest that chemotherapy response in ER-negative patients overexpressing THRβ could be enhanced with a THRβ agonist. Similarly, functional re-activation of ERα by activating THRβ might extend hormonal therapies to these patients as well. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-08-09.
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