# LIN28 and RNA Uridylation in Breast Cancer: Mouse Models and Molecular Analyses

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $336,691

## Abstract

PROJECT SUMMARY / ABSTRACT
A major limitation in finding more effective cancer therapies is the identification and exploitation of novel targets for
rational drug design. Recent and provocative evidence implicates a novel form of post-transcriptional gene regulation
involving 3’ RNA uridylation mediated by Terminal Uridylyl Transferases (TUTases) as a critical gene regulator and
driver of tumorigenesis. These data indicate that dysregulated TUTase activity alone and in concert with the onco-fetal
LIN28/let-7 pathway are hallmarks of poor prognosis in multiple cancer types. Approximately 15% of all cancers
reactivate oncogenic LIN28 expression (either LIN28A or LIN28B) and these cancers are typically characterized by poor
prognosis. Functionally, LIN28 directly blocks the biogenesis of the tumor suppressor let-7 microRNA family. Recently,
we discovered the mechanism behind this blockade. Notably, the TUTase ZCCHC11 through an association with LIN28A
inactivates let-7 by preventing the conversion of precursor let-7 into its mature, tumor suppressor form. In addition,
overexpression of the TUTase ZCCHC11 is implicated in poor prognosis breast cancer independently of the LIN28/let-7
pathway. Strikingly, a recent report has shown that many polyadenylated mRNAs are frequently uridylated at their 3’ ends
in a gene-specific manner and targeted for degradation; however, this observation’s relevance to cancer is currently
unknown. Therefore, our research has three major objectives. The first goal is to develop novel preclinical mouse models
for LIN28-positive breast cancers. These mouse models will elucidate how LIN28 modifies disease progression and will
be an invaluable resource to evaluate new drugs targeted to this cancer type. The second goal is to determine whether
organism-wide loss of Zcchc11 in adult mice has phenotypic consequences using a conditional mouse knockout. Our
published work on conditional inactivation of either Lin28A or Lin28B in adult mice demonstrate that both genes are
dispensable in adults, suggesting that inhibiting either gene is unlikely to cause deleterious side effects in patients. The
last goal is to determine if loss of the TUTase Zcchc11 inhibits Lin28A+/Her2+ and Lin28A-/Her2+ mouse mammary
tumors. This research will be the first proof-of-principle that TUTase loss affects tumors in an immunocompetent
mammal and addresses possible side-effects in cancer patients treated with specific inhibitors of the TUTase ZCCHC11.
This work lays the foundation for new fields of cancer investigations by dramatically shifting the current paradigm to
include TUTases as cancer gene regulators and explores the feasibility of a novel drug class targeted at inhibition of
LIN28 or TUTases. In addition to cancer, our investigation of regulators of the LIN28/let-7 pathway holds significance for
stem cell biology, tissue repair, fertility, growth, glucose metabolism, Type 2 diabetes, and the generation of induced
pluripotent stem cells. Moreover...

## Key facts

- **NIH application ID:** 10215423
- **Project number:** 5R01CA215186-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** John Patrick Hagan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $336,691
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215423

## Citation

> US National Institutes of Health, RePORTER application 10215423, LIN28 and RNA Uridylation in Breast Cancer: Mouse Models and Molecular Analyses (5R01CA215186-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10215423. Licensed CC0.

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