78O_PR The Role of Ap-1 in Endocrine-Resistant Breast Cancer

Abstract

Endocrine resistance is a major clinical issue. AP-1 is a transcription factor downstream of different growth factor receptors (GFR) and stress-related signaling cascades implicated in endocrine resistance. We have previously shown that acquired endocrine resistance is associated with increased AP-1 activity. Moreover, AP-1 modulates the estrogen receptor (ER) transcriptional program, especially upon high GFR signaling. We therefore hypothesized that interfering with AP-1 could circumvent endocrine resistance. Methods and results: AP-1 was genetically inhibited by siRNA or by stable expression of an inducible dominant-negative (DN) c-Jun in MCF7 cells. In vitro, siRNA c-Jun significantly inhibited the growth of acquired tamoxifen resistant (TamR) MCF7 derivatives (>95% inhibition, p = .001) but not of parental cells ( p = .06). Xenografts of two inducible DN c-Jun clones were established in nude mice. Mice were randomized to continued estrogen (E2) supplementation or to either estrogen deprivation (ED) or Tam, all in the presence or absence of DN c-Jun. AP-1 blockade significantly reduced time to tumor response ( p = .014 and p = .006 for the two clones) and time to tumor disappearance ( p = .001 and p = .0034) in the Tam group, with similar results in the ED group. In addition, AP-1 blockade significantly delayed TamR by increasing time to tumor doubling ( p = .002). Furthermore, induction of DN c-Jun resulted in dramatic tumor shrinkage after long-term Tam treatment, suggesting reversal of endocrine resistance with AP-1 blockade. Interestingly, no significant effect was observed on E2-stimulated tumor growth. Immunohystochemistry showed that AP-1 blockade reduced proliferation and induced apoptosis. A gene signature of our TamR MCF7 xenografts significantly overlapped ( p < 2E-16) with a putative gene list associated with EGF-induced ER-DNA binding sites that mostly contain the AP-1 motif. Pathway analysis of these genes identified the AP-1 member c-Fos as the most represented transcription factor. Conclusions: We show that AP-1 blockade increases tumor sensitivity and circumvents resistance to endocrine therapy. We suggest that AP-1 is critical in a switch in the ER transcriptional program and may be a new hallmark of endocrine resistance. Disclosure: All authors have declared no conflicts of interest. Background: Triple negative breast cancer (TNBC), defined by estrogen, progesterone and HER2 negativity, is a heterogeneous disease with limited targeted therapy. Molecular and immunohistochemical stratification have already identified several TNBC subgroups, characterised by different biological processes with possible implication for therapy. A clear picture of the various TNBC entities and their relationship(s), however, is still missing. Aim: To shed light on this problem we have analysed a collection of 111 needle-macrodissected, clinically-annotated TNBCs using an approach based on the integration of DNA copy-number aberrations, transcriptional data and publically available gene signatures. Methods: Allel...

Pathways and biomarkers in breast cancer: latest evidence

“…Inhibition of the transcription factor activator protein 1 potentiates the effect of endocrine treatment and circumvents endocrine resistance L. Malorni (Oncology, Hospital of Prato, Prato, Italy) and colleagues have previously shown that acquired endocrine resistance is associated with increased activator protein 1 [AP-1, a transcription factor downstream of different growth factor receptors (GFRs)] activity and that AP-1 modulates the ER transcriptional programme, especially with high GFR signalling [Malorni et al 2012]. Thus, AP-1 modulation may circumvent endocrine resistance.…”