Sunday, May 18, 2025
5/18/2025
Targeting lineage plasticity to inhibit basal-like breast cancer progression - Basal-like breast cancer (BLBC) accounts for the great majority (70-80%) of triple-negative breast cancer cases. It is a highly aggressive subtype that disproportionately affects younger women and women of African ancestry, leading to disparities in cancer outcomes. BLBC also frequently occurs in women carrying BRCA1 germline mutations. Unfortunately, there are no targeted therapies available for BLBC, and current systemic treatments heavily rely on chemotherapy, which often causes harmful side effects and drug resistance. The aggressive nature of BLBC can be attributed, in part, to its high degree of lineage plasticity and intratumor heterogeneity, posing major clinical challenges. Thus, there is a pressing need to understand the cellular and molecular underpinnings of lineage plasticity in BLBC to develop preventive strategies to intercept its malignant progression. Recent studies have shown that reactivation of embryonic multipotency is a crucial step in the progression of precancerous lesions to malignant BLBC. In this process, oncogenic mutations cause committed luminal progenitor cells to de-differentiate into embryonic multipotent-like (EMP-like) cells resembling embryonic mammary stem cells. Similar EMP-like cells were found to accumulate in breast tissue from women with germline BRCA1 mutations. Importantly, inhibiting this process by genetically deleting a key transcription factor, SOX9, blocks de-differentiation and the progression of premalignant lesions to BLBC, highlighting the potential of targeting dedifferentiation to multipotency as an effective strategy for intercepting breast cancer progression. However, the underlying mechanisms driving de-differentiation and the targets for de-differentiated cells remain largely unknown. In this project, we will define the key de-differentiated cells required for BLBC progression and explore strategies targeting these cells for cancer interception (Aim 1). We have identified several novel intermediate cell states during BLBC transformation and specific markers for EMP-like cells. Based on these new insights, we will define the intermediate cell states critical for BLBC progression by using a combination of transplantation and in vivo cell ablation approaches. We will determine the relevance of these cell states in breast tissue of BRCA1 mutation carriers, who are predisposed to developing BLBC, and explore therapeutic strategies to target dedifferentiated cells for BLBC interception. Additionally, we will elucidate the molecular mechanisms driving dedifferentiation to multipotency in BLBC (Aim 2). We will utilize mouse and human breast organoid culture and in vivo organoid transplantation models to investigate the functional role of YAPTAZ-SOX9 in multipotency reactivation. We will determine the role of SOX9 downstream pathways in promoting lineage plasticity and how SOX9 controls the stemness-related transcriptional program. Intercepting cancer progression by eliminating precancerous cells that are critical for malignant transformation is a highly desirable approach for preventing and treating cancer at its earliest stages. It has the potential to greatly reduce the morbidity and mortality associated with cancer, as well as the cost of cancer care.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).