Role of LBH in the Etiology of Basal-Subtype Triple-Negative Breast Cancer
Abstract
Basal subtype triple-negative breast cancer (lacking estrogen and progesterone hormone receptors and HER2 amplification; hereafter TNBC) is the deadliest breast disease, often affecting young women. Unfortunately, it cannot be treated with hormonal therapy or Herceptin and few other specific treatments exist. TNBC are highly metastatic tumors, enriched in undifferentiated cancer stem cells that fuel cancer, metastasis, and resist chemo/radiotherapy. Consequently, resistance to chemotherapy and radiation is rapid, and most TNBC patients relapse and die within 3-5 years after diagnosis. Thus, novel, more effective therapies are urgently needed. This grant addresses an innovative, clinically highly relevant problem in breast cancer biology, i.e., how clinically aggressive, treatment-refractory basal-like TNBC breast cancers are formed from more differentiated luminal tumor cells. The mammary gland consists of two major epithelial cell lineages: luminal cells that line the ducts of the mammary gland, express hormone receptors, and differentiate into milk-producing cells and basal cells that form the outer basal myoepithelial layer of the mammary gland and harbor multi-potent mammary stem cells responsible for tissue regeneration. While it has been established that basal-like TNBC breast cancers originate from luminal cells, similar to less aggressive breast cancer types, the factors that mediate luminal to basal dedifferentiation within cancer cells during TNBC development and rapid progression remain largely unknown, hampering the development of new TNBC subtype-specific treatments. Advances into the molecular mechanisms governing normal mammary gland development have rendered many breakthroughs in breast cancer biology and treatment in the past. The Principal Investigator of this application has pioneered the discovery of Limb-Bud-and-Heart Homologue (LBH), a novel breast stem cell- and basal mammary cell-promoting transcriptional regulator that we showed is required for mammary gland development. Significantly, we showed LBH is aberrantly overexpressed in over half (55%) of TNBC tumors, and this correlates with reduced metastasis-free patient survival. However, the consequences of aberrant LBH overexpression in breast tumorigenesis have not yet been investigated. Interestingly, in breast development, LBH is one of only few factors capable of promoting an undifferentiated, basal mammary stem cell state. Furthermore, we showed LBH represses luminal cell differentiation and gene expression, foremost the expression of estrogen hormone receptor (ER), a key therapeutic target that is lacking in TNBC. Objectives: This grant proposes to investigate preliminary findings suggesting LBH may have a novel pro-oncogenic role in breast cancer as a mediator of lineage commitment and mammary differentiation. Specifically, we postulate that aberrant LBH activation may drive the formation of basal subtype TNBC from luminal, ER+ breast epithelial cells and their rapid progression into deleterious cancer stem cells. In breast cancer cell lines and unique breast cancer subtype-specific, patient-derived breast cancer cell models, we will test if introduction of LBH into luminal, ER+ breast cancer cells induces a luminal-to-basal switch, de-differentiation into cancer stem cells, as well as endocrine resistance through LBH-mediated loss of ER. Conversely, we will test if abrogation of LBH expression in basal TNBC tumor cells induces a more differentiated luminal tumor phenotype, with upregulated ER expression that may sensitize TNBC tumors to ER-targeted drugs. Finally, this grant will test for the first time if down modulation of LBH in human breast cancer tumors grown in mice targets and impairs cancer stem cell activity and opposes metastasis. This grant, if successful, will identify LBH as a novel key molecular determinant that drives the development and progression of highly aggressive basal subtype triple-negative b
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910255
Entities
People
- Karoline Briegel
Organizations
- United States Army
- University of Miami