# Deciphering the role of Six2 in regulating cancer stem cell properties and promoting late-stage metastasis in breast cancer.

> **NIH NIH K00** · HARVARD MEDICAL SCHOOL · 2021 · $93,078

## Abstract

Project Summary. The vast majority of breast cancer-related deaths are not caused by the primary tumor, but
rather by metastases. Current studies mainly focus on the prevention of the early stages of metastasis.
However, since tumor cells have likely left the primary tumor at diagnosis, inhibiting early stages of metastasis
may not be the most effective way to inhibit metastatic burden. Therefore, an emphasis on developing
therapeutics against late-stage metastasis is essential for improving survival in breast cancer patients. To
better understand this complex process, I am examining the role of the developmental transcription factor Six2
in promoting metastatic burden. Six2 is a member of the Six family of transcription factors that are not only
critical for development, but also for tumor progression and metastasis. Six2 is unique because it specifically
affects the later stages of breast cancer metastasis, demonstrating its potential as a therapeutic target to
decrease metastatic burden. My studies thus far have revealed novel roles for Six2 in breast cancer. I have
shown that Six2 upregulates the expression of numerous stem cell-related genes, including a master regulator
of stemness, Sox2. Six2 also increases the mammary stem cell population, as well as tumor-initiation in vivo.
My data demonstrate for the first time that cancer cells may hijack Six2 to perform its developmental stem cell
roles out of context, and that this role of Six2 may contribute to its ability to induce metastatic outgrowth.
 In this F99/K00 proposal, I outline a strategy to complete my dissertation studies, as well as how I will
prepare to move on to a postdoctoral position. In Aim 1, I will describe my current findings regarding the role of
Six2 in regulating stem cell phenotypes to promote late-stage metastasis. In Aim 2, I will outline my research
strategy to complete my predoctoral studies, which will use stage-specific in vitro/in vivo models in combination
with a comprehensive bioinformatics-driven candidate gene approach to continue to examine the role of Six2 in
the later stages of metastasis. This approach will lead to the discovery of additional downstream effectors that
could be targeted therapeutically to inhibit metastatic burden. Lastly, Aim 3 outlines my plans for postdoctoral
research, and how I will identify an ideal postdoctoral mentor who will provide additional training in in vivo
microscopy, single-cell analysis approaches and in vitro/ex vivo tissue-specific microenvironment engineering
to examine other aspects of late-stage metastasis including how the microenvironment regulates the activity of
metastasis-initiating cells (MICs). In addition, I will seek out an environment in which translational research is
encouraged, as well as my continued commitment to academics and teaching. My current and future training,
along with my dedication to cancer biology education and mentoring, is well aligned with the goals of the
National Cancer Institute of p...

## Key facts

- **NIH application ID:** 10242740
- **Project number:** 5K00CA223023-05
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Michael UJ Oliphant
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $93,078
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242740

## Citation

> US National Institutes of Health, RePORTER application 10242740, Deciphering the role of Six2 in regulating cancer stem cell properties and promoting late-stage metastasis in breast cancer. (5K00CA223023-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242740. Licensed CC0.

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