Elucidating the Lineage Dependency of Triple-Negative Breast Cancer
Abstract
Triple-negative breast cancer (TNBC) is an aggressive cancer subtype that has poor prognosis. Due to lack of targeted therapy, the systemic treatment of TNBC mainly relies on chemotherapy that has harmful side effects and a high rate of drug resistance. Thus, there is a pressing need to identify fundamental vulnerabilities of TNBC that are broadly applicable. We propose to study a new type of cancer vulnerability that is associated with the tissue origin of the cancer, which is called lineage dependency. Indeed, such type of lineage dependency has been the basis of endocrine therapy for estrogen receptor (ER)-positive breast cancer. Thus, elucidating the lineage dependency of TNBC is likely to yield a new class of effective therapeutic targets. Our preliminary studies have identified one promising TNBC lineage dependency controlled by a stem cell factor called SOX9. We found SOX9 plays a crucial role in the development of stem cells giving rise to TNBC, and it is required for progression of benign ductal carcinoma in situ (DCIS) to malignant TNBC. We have also found cancer cells that have high levels of SOX9 are particularly aggressive and may be the cause of drug resistance. In this proposal, we will use sophisticated tumor models to study the following specific aims: (1) How does SOX9 mechanistically control the progression of DCIS to malignant TNBC? (2) Whether inactivating SOX9 can be an effective approach for treating TNBC tumors. (3) Whether eliminating SOX9-expressing cancer cells can overcome drug resistance. Achieving the above specific aims will have direct impact on at least two Breast Cancer Research Program Overarching Challenges: (1) Identify what drives breast cancer growth; determine how to stop it. (2) Identify determinants of breast cancer initiation (particularly invasive cancer initiation). Because the SOX9-driven growth and survival mechanism is engrained in the cellular origin of TNBC, it is likely to be a common vulnerability shared by many TNBC tumors, as well as by various malignant cell clones within a given patient. Thus, our studies will help develop a new therapeutic paradigm that targets the fundamental lineage dependency of TNBC. In addition, our work will help discover useful biomarkers that may help distinguish indolent and aggressive DCIS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810445
Entities
People
- Wenjun Guo
Organizations
- Albert Einstein College of Medicine
- United States Army