Significant advances have been achieved in the treatment of breast cancer; however, the prognosis for patients with brain metastasis remains dismal, with extremely short survival times. Up to 30% of patients with advanced breast cancer develop brain metastases, and management strategies for such patients continue to be a major clinical challenge. Finding novel therapies to prevent and treat brain metastases requires an understanding of the biology and molecular basis of brain metastasis, which currently is constrained by a dearth of experimental models and specific therapeutic targets. We recently developed mouse models in which tail-vein injection of two inflammatory breast cancer (IBC) cell lines led to a high rate of brain metastasis (67%), a substantial improvement over previous xenograft models. Notably, knockdown of miR-141, a microRNA we found to be overrepresented in IBC cell lines and patient samples, specifically blocked brain metastasis without affecting lung metastasis. We also generated clones from the brain metastases that showed very high expression of miR-141 compared with lung metastasis-derived clones. However, it is unknown whether miR-141 is sufficient to generate a high rate of brain metastasis via tail-vein injection of all breast cancer cell lines, and it is unclear how modulation of miR-14 blocks brain metastasis.
The aims of the work proposed here address the hypothesis that miR-141 has a significant role in promoting metastatic colonization to the brain and can serve as a viable target for prevention of brain metastasis. Studies under Aim 1 will determine if miR-141 mediates brain metastasis of a broad range of IBC and non-IBC cell lines and whether miR-141 is sufficient for metastasis seeding via tail vein injection into mice.
Aim 2 will identify mechanitic insights into how miR-141 inhibition significantly suppresses brain metastatic colonization and identify therapeutic targets taking advantage of our unique in vivo and in vitro brain metastasis models. We will further test the therapeutic efficacy of systemically administered anti-sense miR-141 in the prevention and treatment of brain metastases in our xenograft models. The proposed research is relevant to public health because it has the potential to identify novel targets and develop novel strategies to prevent and treat brain metastasis from breast cancer and thereby improve outcomes for patients with breast cancer.
Our goal in this project is to elucidate the role of the microRNA miR-141 in mediating brain metastasis and to demonstrate its potential utility as a therapeutic target. The proposed research is relevant to public health because it has the potential to identify novel targets and develop novel strategies to prevent and treat brain metastasis from breast cancer and thereby improve outcomes for patients with breast cancer.
|Smith, Daniel L; Debeb, Bisrat G; Thames, Howard D et al. (2016) Computational Modeling of Micrometastatic Breast Cancer Radiation Dose Response. Int J Radiat Oncol Biol Phys 96:179-87|
|Debeb, Bisrat G; Lacerda, Lara; Anfossi, Simone et al. (2016) miR-141-Mediated Regulation of Brain Metastasis From Breast Cancer. J Natl Cancer Inst 108:|