FIP200 and Rb1 expression in CNS metastasis from breast cancer (CNS met): Potential predictors of patient outcome

• Published in: Journal of clinical oncology Vol. 30; no. 15_suppl; p. 2014
• Main Authors: Hashemi Sadraei, Nooshin, Ulasov, Ilya, Burgett, Monica, Nowacki, Amy S, Prayson, Richard, Weil, Robert J., Kar, Niladri, Ahluwalia, Manmeet Singh, Muller-Greven, Ga‘lle, Shi, Ting, Lesniak, Maciej S., Gladson, Candece
• Format: Journal Article
• Language: English
• Published: 20.05.2012
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2012.30.15_suppl.2014

Abstract only 2014 Background: Patients with CNS met have a poor outcome with significant variation in overall survival. No marker to predict survival exists. Rb1 is a negative regulator of the cell cycle, and FiP200 is an upstream signaling node that is distributed between the nucleus and cytoplasm. Nuclear FIP200 inhibits cell proliferation by promoting expression of Rb1, whereas cytoplasmic FIP200 promotes cell survival through autophagy. Previously FIP200 deletion/mutation has been reported in 20% of primary invasive breast cancer [BR ca] patients. FIP200 cellular localization and genetic alterations have not been examined in CNS met. Methods: A retrospective analysis of BR ca and CNS met was performed based on tissue availability from 2 institutions. FIP200 and Rb1 expression and localization was evaluated by immunohistochemistry. Genetic alterations were evaluated by DNA array analysis. Results: 80 patients (42 BR ca and 38 CNS met) were identified. Overall CNS met samples had significantly higher levels of cytoplasmic FIP200 as compared to BR ca (52% vs 24% respectively, p=0.0002) and increased expression of FIP200 around areas of hypoxia/necrosis, consistent with increased autophagy. There was also a significant increase in expression of nuclear FIP200 and Rb1 in the CNS met compared to BR ca (p=0.0007 and p=0.0055 respectively). Median survival from development of CNS met was longer in the group with high levels of nuclear Rb1; 14 (3-27) vs 20 (12-33) months (low expression < 20% vs high ≥ 20%, p=0.1). The same finding was observed with FIP200, longer survival was observed with high nuclear expression; 16 (7-33) vs 19 (0.4-27) months (low expression <20% vs high ≥ 20%, p=0.2). Our DNA analysis for copy number variation and LOH in CNS met revealed no deletion in Rb1 or FIP200. Conclusions: The pattern of expression of Rb1 and FIP200 in CNS met is different from BR ca. Notably, cytoplasmic FIP200 which promotes cell survival is highly expressed in CNS mets vs BR ca. This suggests metastatic breast cancer cells utilize autophagy as a survival mechanism. In addition, there is a trend to better survival of those patients with CNS met who express high nuclear FIP200 and Rb1, both of which have anti-proliferative roles in the nucleus.