# Roles of long-non-coding RNA, XIST, in brain metastasis of breast cancer

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $449,057

## Abstract

During the late stage, 20-30% of patients with breast cancer develop brain metastasis and the one year survival
rate of these patients is less than 20%. Therefore, it is of paramount importance to elucidate the molecular
mechanism involved in the metastatic process in order to define a specific therapeutic target. Long non-coding
RNAs (lncRNAs) that are distinguished from other small RNAs have recently drawn strong attention for their
critical roles in tumor progression. We have examined the expression profile of lncRNAs in tumor tissues from
primary and brain-metastatic lesions of breast cancer patients using our newly constructed lncRNA library. We
found that (i) brain metastatic lesions express significantly lower amount of the lncRNA, XIST, which is linked to
the X chromosome and plays a critical role in the X chromosome inactivation, (ii) when XIST was silenced in
breast cancer cells, such cells significantly promoted brain metastatic growth in mice, and (iii) XIST expression
presented a significant reverse correlation with brain but not with bone metastasis in patients. Therefore, we
hypothesize that the loss of XIST promotes brain metastasis of breast cancer by stimulating EMT and
self-renewal of tumor initiating cells through activation of the PLS3 and c-met pathways in the brain
microenvironment. We also hypothesize that PTER suppresses metastatic ability of tumor initiating cells
by blocking the c-Met pathway. To test these hypotheses, we will elucidate the molecular pathway through
which loss of XIST stimulates the EMT by activating PLS3 on the X-chromosome (Aim 1). We will also
decipher the mechanism by which the loss of XIST activates the c-Met pathway thereby promoting stemness of
the metastasis initiating cells (Aim 2). Finally, we will test the efficacy of PTER or cabozantinib on metastasis
initiating cells using xenograft, PDX and genetic mouse models (Aim 3). We believe that the outcome of our
study will provide a paradigm shift in our current understanding of the pathology of brain metastasis and also
have a significant impact on the future treatment of this devastating disease. The results of this study will
significantly impact on this research field in three ways. First, we found that XIST plays a pivotal role in
metastasis initiating cells in brain metastasis of breast cancer. XIST is known for its critical function for X
inactivation and for modulation of pluripotency of embryonic stem cells; however, how this lncRNA is involved in
tumor progression is virtually unknown. Therefore, the results of this project will reveal a novel pathological
mechanism of tumor metastasis and provide a paradigm shift in our understanding of breast cancer
progression. Secondly, we propose to decipher the pathway of reciprocal communication between metastasis
initiating cells and astrocytes in the brain microenvironment and their roles in the metastatic progression, which
we believe, will lead to a discovery of a novel therapeutic target. Fin...

## Key facts

- **NIH application ID:** 10073330
- **Project number:** 5R01CA205067-05
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Kounosuke Watabe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $449,057
- **Award type:** 5
- **Project period:** 2017-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073330

## Citation

> US National Institutes of Health, RePORTER application 10073330, Roles of long-non-coding RNA, XIST, in brain metastasis of breast cancer (5R01CA205067-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073330. Licensed CC0.

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