Breast cancer is a highly heterogeneous disease and breast cancer metastasis is responsible for most cancer related mortality. Recent studies suggest different cellular origins and early transformation events may influence metastasis behavior of the resulting tumors. Therefore, it is important to understand molecular changes during early stages of cancer to develop better treatment options. In addition, it has also been suggested that normal signaling pathways during development are often deregulated during cancer, suggesting a conserved mechanism. The overall goal of this project is to study the role of transcription factor Elf5 during initiation of breast cancer. Elf5, a key luminal differentiatio marker, has been shown to play an important role in inhibiting mammary stem cells during normal mammary gland development by repressing important cell fate regulators such as Slug and Notch signaling. Also, recent studies highlighted an EMT inhibitory and anti-metastatic role of Elf5 in breast cancer metastasis to lung by repressing Slug. Although these studies indicate a prominent role of Elf5 in cancer metastasis, functional involvement of Elf5 in earlier stages of the tumorigenesis remains elusive. We hypothesize that the loss of Elf5 expression will promote tumor initiation by allowing the expansion of Elf5 negative tumor initiating cells (TICs) through de- differentiation or attenuation of negative selection. To test this hypothesis, I will first conirm the tumor suppressive role of Elf5 in different subtypes of tumor using mouse breast cancer models. I will also perform lineage tracing of Elf5 positive cells for the first time using a novel Elf5-reporter mouse strain to interrogate how Elf5 behaves during tumor initiation and progression. I will directly test the effect of Elf5 loss on tumor initiating cells (TICs) using standard markers to identify such population in tumors. Following phenotypic characterization, I will then determine the molecular mechanism of Elf5 in negative regulation of tumor initiation. During my independent phase, I will also validate my experimental results using patient-derived xenograft samples. I will perform functional studies with Elf5 and its potential target genes in tumor initiation in patient derived xenograft (PDX) tumors. From all these studies, I will try to establish a crucial function of Elf5 on TICs and reveal its potential function in influencing tumor initiation. This study combines my previous training in developmental biology with my current training in breast cancer. This allows me to establish and develop my scientific credentials in a new field investigating the role of key cell fate regulators such as Elf5 in breast cancer progression. My study will contribute significantly to the current understanding of molecular changes during early steps of cancer initiation and may possibly develop novel therapeutics to target cancer during early stages.
Regulators of the cell fate in the mammary gland lineage are prime candidates as regulators of breast cancer initiation and progression due to their ability to share common signaling pathways. In this study, I will elucidate function of key cell lineage regulator, Elf5 in early staes of breast cancer initiation. These results will further enhance our knowledge on cellular and molecular mechanism during early stages of breast cancer and facilitate the development of potential future targeted therapy.
| Chakrabarti, Rumela; Celià-Terrassa, Toni; Kumar, Sushil et al. (2018) Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche. Science 360: |
