Molecular Changes Associated with Initial Steps of Breast Cancer Metastasis for Risk Stratification and Therapy Development
Abstract
The most feared outcome for a patient after breast cancer diagnosis is the development of metastatic disease, i.e., when breast cancer spreads to other organs such as liver, lung, and bone. When breast cancer becomes metastatic, it is virtually no longer curable. Treatment at this point on will be primarily palliative in nature. Our work addresses the overarching challenge of identifying what drives breast cancer metastasis and identify why some breast cancers become metastatic breast cancers. Ninety percent of death for a patient after a breast cancer diagnosis is due to development of metastatic disease. Despite advances in treatments, the survival of patients with metastatic breast cancer has not changed much over the past decades. Our work aims to identify molecular determinants that initiate and/or promote breast cancer spread and their mechanisms of action in the process. Our work will lead to better risk stratification and optimal therapy selection in the adjuvant discussion and development of novel therapy to prevent and cure metastatic breast cancer eventually. Breast cancer metastasis is a complicated process. Breast cancer cells have to grow first, invade into neighboring tissues outside the milk ducts, recruit and stimulate new blood vessel formation to supply oxygen and nutrient to sustain local tumor formation, invade into blood vessels (or lymphatic channels), travel and survive in the blood (or lymphatic) circulation, arrest at a distant destination and exit the circulation, adapt to the new environment, grow to form microscopic tumor, and recruit and stimulate new blood vessel formation to meet oxygen and nutrient demand of the growing metastatic tumor. If a patient has been treated with anti-cancer therapy during the process, tumor cells have to also evolve to acquire resistance to therapy to survive and grow to form tumors. Needless to say, multiple molecules are involved in this process, making it difficult to study. Modern sophisticated technologies have been applied to address the question of cancer metastasis. We are able to decipher the entire genetic codes of a breast tumor expediently and at an affordable cost. We are also able to analyze the huge amount of genetic information intelligently. Such efforts have been applied systematically to study multiple cancer types including breast cancer. More than 800 primary breast cancers obtained at initial breast surgeries have been sequenced and analyzed by the Tumor Cancer Genome Atlas (TCGA). Despite this, the molecules involved in orchestrating breast cancer metastasis remain largely elusive. Here we propose the following model system to examine the mechanism of breast cancer metastasis. We will investigate synchronous bilateral breast cancers. Synchronous bilateral breast cancers are bilateral breast cancers that are diagnosed within a short while of each other from the same patient. We have completed deep sequencing of nine pairs of such breast cancers and found the majority, if not all, are the result of breast cancers forming in one breast and then spreading to the contralateral breast. In these "breast to breast" metastases, there is no need to accrue additional molecular changes to adapt to a new tissue environment as seeding breast cancer cells are returning to a familiar terrain: the breast tissue. Since there is no exposure to systemic therapy, there is no selection pressure for development of drug resistance. These "breast to breast" metastases represent a focused and streamline system to study the molecular mechanisms of the initial steps of metastasis. We find indeed there are only a very limited number of molecular changes that are acquired when a mother tumor gives rise to a daughter tumor. These changes are excellent candidate genes for metastasis. Reassuringly, some of the genetic alterations we identified so far have already been implicated in cancer metastasis. Moreover, recurrent changes in genes with si
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610546
Entities
People
- Shiuh-wen Luoh
Organizations
- Portland VA Research Foundation
- United States Army