BCLxL in ER+ Breast Cancer Bone Metastasis
Abstract
Overarching Challenge: Identify why some breast cancers become metastatic; eliminate the mortality associated with metastatic breast cancer. Bone is the most common site of metastasis of ER+ breast cancer, accounting for 45% of cases compared to 19% in the lungs, 5% in liver, and 2% in brain. Once clinically detected, bone metastasis is incurable and is a major cause of death. Yet, very little is known about the mechanisms explaining how breast cancer spreads to the bone. Such knowledge can help design a more effective strategy to prevent and treat bone metastases. While pursuing our CDMRP-funded project on the Bcl-xL protein in breast cancer lung metastasis, we made an unexpected finding. The estrogen receptor-positive (ER+) breast cancer cell line MCF7 is the most commonly used breast cancer cell line, especially for studying ER+ breast cancer. We found that endocrine therapy could cause this cell line to produce high levels of Bcl-xL. When we used a genetic method to prevent this protein from being produced, MCF-7 cells became more sensitive to endocrine treatment. We also found that forcing the genetic materials encoding the Bcl-xL protein into MCF7 cells caused these cells to dramatically enhance their ability to metastasize to the bone in mice. Conversely, when a genetic method is used to prevent these cells from producing Bcl-xL, metastasis to the bone is significantly reduced. These preliminary data suggest that BCLxL may provide survival and other metastasis-instigating functions during bone metastasis. Together, these preliminary data suggest the following hypothesis: Bcl-xL contributes to ER+ breast cancer bone metastases and mediates their resistance to endocrine therapy, and inhibition of the Bcl-xL function suppresses ER+ breast cancer bone metastases and sensitizes them to endocrine therapy. We will test this hypothesis by pursuing three specific aims. Aim 1 will test whether forcing ER+ breast cancer cells to make excessive amounts of Bcl-xL causes accelerated formation of bone metastasis, using multiple advanced and clinically relevant rodent models of ER+ breast cancer, including a rat model of ER+ breast cancer. Aim 2 will examine whether inhibiting the activity of Bcl-xL in ER+ breast cancer cells will suppress bone metastasis and will also sensitize ER+ bone metastases to the standard-of-care endocrine therapies. Aim 3 will discover the molecular mechanisms by which Bcl-xL promotes ER+ breast cancer bone metastasis and endocrine resistance. Impact: Bone metastasis is an area poorly studied and understood in breast cancer research. This hypothesis has important implications for understanding how breast cancer spreads to the bone, and how breast cancer becomes resistant to endocrine therapy. The successful completion of the proposed work could lead to better treatment for preventing or treating bone metastasis in breast cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010403
Entities
People
- Yi Li
Organizations
- Baylor College of Medicine
- United States Army