Abstract 678: Lunatic Fringe and p53 cooperatively prevent development of claudin-low breast cancer
Authors: Wen-Cheng Chung, Shubing Zhang, Keli Xu
Journal: Cancer Research (2016)

Abstract Claudin-low breast cancer (CLBC) is a poor prognosis disease that disproportionately affects younger patients and women with African ancestry, causing significant morbidity and mortality due to chemoresistance and lack of targeted therapy. CLBC shows stemness and mesenchymal features, and is thought to have originated from mammary stem cells. However, little is known on how these tumors initiate and progress. We previously reported that deletion of Lunatic Fringe (Lfng), a modulator of Notch signaling, in the moue mammary epithelial cells induced development of mammary tumors, among them two-thirds are basal-like breast cancer and one-third resemble human CLBC. Deletion of p53 in combination with other mutations (inactivation of Rb or overexpression of oncogenic c-Met) also resulted in mammary tumors with mesenchymal features. We hypothesize that Lfng and p53 may cooperate to suppress CLBC initiation and progression. To this end, we have generated mammary-specific deletion of Lfng and p53 using MMTV-Cre. The vast majority of Lfngflox/flox;p53flox/flox;MMTV-Cre mice succumbed to lymphoma by 3-5 months of age before mammary tumor onset, likely due to the leaky deletion in B- and T cells. Interestingly, deletion of both copies of Lfng and one copy of p53 (Lfngflox/flox;p53flox/+;MMTV-Cre) dramatically accelerated mammary tumor development compared to the Lfngflox/flox;MMTV-Cre model, with the median tumor-free survival shortened from 600 days to 191 days. Of note, all mammary tumors from the Lfngflox/flox;p53flox/+;MMTV-Cre mice were consisted of mesenchymal/spindle-shaped cells and expressed markers of epithelial-mesenchymal transition (EMT), suggesting that deletion of one copy of p53 caused a shift of tumor subtype from basal-like to claudin-low. We found that deletion of Lfng caused up-regulation of E-cadherin in the mammary gland, whereas additional deletion of one copy of p53 decreased E-cadherin but dramatically increased vimentin levels, suggesting that p53 haploinsufficiency promotes EMT in this context. Compared with the wild type gland at 3 months of age, Lfngflox/flox;p53flox/+;MMTV-Cre mutant gland showed down-regulation of Notch downstream targets including Hes5, Hey1, and Hey2, suggesting reduced Notch signaling. Given that Notch signaling is known to restrict mammary stem cell expansion, down-regulation of Notch signaling may lead to inappropriate accumulation of mammary stem cells during CLBC initiation. Taken together, our results reveal genetic interaction between Notch and p53 in the pathogenesis of CLBC. Moreover, we have established a new mouse model for CLBC with complete penetrance and accelerated tumor onset, providing an ideal tool in defining molecular events leading to the initiation and progression of CLBC as well as identifying potential therapeutic targets for this poor prognosis disease. Citation Format: Wen-Cheng Chung, Shubing Zhang, Keli Xu. Lunatic Fringe and p53 cooperatively prevent development of claudin-low breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 678.