Abstract P1-13-13: Nuclear envelope Expression of the Oncogene Adipocyte-Associated Methionine Domain Containing Conveys Inferior Prognosis but Increased Sensitivity to Statins and Fluorouracil-Based Therapy

Abstract

Abstract The sub-classification of invasive breast cancer into Integrated Clusters by a combined analysis of genomic change and expression profiling has revealed novel cancer drivers. The integrated Cluster 2 breast cancer sub-group represents a cohort with aggressive, largely estrogen receptor positive tumours with a high relapse rate. It is characterized by an amplification of chromosome 11 at the heart of which is a little studied gene which codes for the protein Adipocyte-Associated Methionine Domain Containing (AAMDC). Initial cell line and murine studies demonstrated oncogenic behaviours for AAMDC including increased proliferation and invasion, increased colony formation and anti-estrogen resistance. Downstream gene expression analysis showed the protein to modulate cholesterol biosynthesis, one carbon metabolism and mTOR signaling. To assess the clinical impact of differing levels and sub-localizations of AAMDC, immunohistochemistry for AAMDC was carried out using tissue microarrays from a cohort of 420 patients with invasive breast cancer. Expression was noted in a number of sub-cellular localizations including diffuse cytoplasm, nucleus and nuclear envelope. Using both dichotomous and continuous scoring, no significant association for any expression site with standard prognostic factors was identified including size, lymph node status, grade or receptor statuses. However, both cytoplasmic and nuclear envelope expressions correlated with significantly worse overall survival (p=0.04 and p=0.04 respectively) whereas nuclear expression showed a trend to better survival (p=0.06). Distant relapse and breast cancer deaths were lowest where there was nuclear expression but no nuclear envelope expression (4.7% and 4.7% respectively) but significantly higher for the reverse expression pattern (18.9%, p=0.02 and 17.6%, p=0.03 respectively). Considering the pre-clinical impact of AAMDC on genes involved in cholesterol biosynthesis, we studied the effects of statin prescription in the early disease setting in the context of AAMDC expression. Statins were found to be generally protective of relapse across the group. Only nuclear envelope AAMDC expression interacted, with a hazard ratio (HR) of 0.33 for distant relapse with high expressors, compared to a HR of 0.90 in low expression (p=0.02 for difference). Similarly, considering one carbon metabolism, we explored the impact of the anti-metabolite drug capecitabine compared to other chemotherapy treatments, largely taxane-based, in the metastatic setting. Again, only nuclear envelope expression interacted with median progression-free survivals on capecitabine of 2.0 v 12.2 months for low and high nuclear envelope expression respectively, p=0.03. In summary, AAMDC nuclear envelope expression correlates with poor prognosis which may be mitigated by statin administration in the early disease setting. This expression pattern also confers sensitivity to flurouracil-based metastatic treatment. Citation Format: Andrew D. Redfern, Indunil Weerasena, Lisa Spalding, Monique Ong, Emily Golden, Eleanor Woodward, Pilar Blancafort. Nuclear envelope Expression of the Oncogene Adipocyte-Associated Methionine Domain Containing Conveys Inferior Prognosis but Increased Sensitivity to Statins and Fluorouracil-Based Therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-13.