Abstract 2894: Notch signaling promotes survival and recurrence of dormant mammary tumor cells following HER2/neu targeted therapy
Authors: Abravanel Daniel L. , Collins Meredith A. , Belka George K. , Pan Tien-chi , Pant Dhruv K. , Sterner Christopher J. , Chodosh Lewis A. 
Published: August 2015

Breast cancer remains the leading cause of cancer-related deaths among women despite significant improvements in diagnosis and treatment. Mortality is principally due to the propensity of breast cancers to recur from reservoirs of local and disseminated residual tumor cells that survive therapy. Importantly, breast cancers can recur after long periods of clinical remission, implying that at least some breast cancers pass through a dormant phase prior to relapse. However, little is known about the signaling pathways that permit residual tumor cells to survive in a dormant state and eventually resume growth. Development of effective therapeutic interventions will require more detailed understanding of these fundamental processes in tumor biology.

Our laboratory has developed a series of mouse models that permit the conditional activation of oncogenes in the mammary glands of mice and can be used to recapitulate key features of breast cancer progression including dormancy and recurrence after targeted therapy. In the MMTV-rtTA;TetO-neu (MTB/TAN) model, treatment with doxycycline permits mammary specific activation of HER2/neu and drives primary tumor formation. Upon removal of dox and resultant down-regulation of HER2/neu, primary tumors regress as a consequence of oncogene addiction. However, a small population of tumor cells persists in a histologically identifiable residual lesion. After a period of cellular dormancy, residual tumor cells re-enter the cell cycle in a stochastic manner and give rise to recurrent tumors, independent of HER2/neu signaling.

Combining this model for recurrent mammary tumorigenesis with bioinformatics analyses of breast cancer patients, we now identify a role for Notch signaling in the recurrence of HER2/neu-driven mammary tumors. We find that Notch signaling is acutely up-regulated in tumor cells following HER2/neu pathway inhibition and that Notch activation is both necessary and sufficient for the survival and recurrence of dormant residual tumor cells that persist following HER2/neu blockade. Consistent with this, computational analysis revealed that Notch pathway activity is an independent prognostic factor for breast cancer recurrence in patients. Together, these results implicate Notch signaling in the survival and recurrence of dormant residual tumor cells and identify dormancy as a discrete, targetable stage of breast cancer progression. Therapeutics targeting Notch could address the unmet need for treatments directed against minimal residual disease for the prevention of breast cancer recurrence.

Citation Format: Daniel L. Abravanel, Meredith A. Collins, George K. Belka, Tien-chi Pan, Dhruv K. Pant, Christopher J. Sterner, Lewis A. Chodosh. Notch signaling promotes survival and recurrence of dormant mammary tumor cells following HER2/neu targeted therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2894. doi:10.1158/1538-7445.AM2015-2894