Abstract 2149: Cooperation of Notch and RAS/MAPK pathway leads to poor outcome in breast cancer patients

Abstract

Abstract Breast cancer is a leading cause of cancer-related deaths in women the world over, particularly in the Western population. However, emerging trends indicate an alarming rise in breast cancer incidences in other parts of the world including India. A major impediment in breast cancer treatment is occurrence of metastasis leading to poor prognosis and survival in certain patients. Therefore understanding the molecular pathways responsible for such phenomenon is critical. Recent studies have implicated aberrant Notch signaling in breast cancers. We undertook an extensive study analysing the expression of the Notch pathway members in breast biopsies of Indian origin. We observed increased expression of several Notch receptors including Notch 1, 2 3, and 4, Notch-ligands including Jagged1, Jagged2, and Delta-like 4, and downstream targets of the Notch pathway Hes1/Hes5 in breast cancer tissues compared to the normal counterpart. Additionally, we detected cleaved (active) Notch1 and Hes1/5 in early precursors of breast cancers - hyperplasia and ductal carcinoma in situ - suggesting that aberrant Notch activation may be an early event in breast cancer progression. In in vitro transformation experiments, we observed that while constitutively active Notch1 alone failed to transform HMLE immortalized breast cells, it synergized with the Ras/MAPK pathway to mediate transformation in vitro. Interestingly, compared to only cleaved Notch positive cases, those positive for both pERK1/2 and Notch showed poor survival, and majority of such cases were triple negative breast cancers. This suggests that in highly aggressive triple negative breast cancers that exhibit poor survival, the Notch and Ras/MAPK pathway cooperation might play a crucial role and thus targeting these two pathways together might offer a novel therapeutic strategy for this aggressive form of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2149. doi:1538-7445.AM2012-2149