# Determining the roles of the Hippo pathway kinases LATS1 and LATS2 in mammary gland homeostasis and disease

> **NIH NIH F31** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $46,036

## Abstract

Project Summary
Breast cancer is the most prevalent cancer among women worldwide. The basal-like subtype of breast cancer
is associated with a particularly poor prognosis, yet the molecular mechanisms leading to the origin and
pathogenesis of this disease are inadequately understood. Our data has indicated that the Hippo signaling
pathway is an important regulator of cell fate and progenitor status in the mammary epithelium. Central to Hippo
pathway signaling are the transcriptional regulators YAP and TAZ (YAP/TAZ), which when localized to the
nucleus drive transcriptional events that are required for basal stem cell traits. Nuclear YAP/TAZ activity is
restricted through the tumor suppressor kinases LATS1/2, which are required to maintain homeostasis in the
mammary epithelium. LATS1/2 have been shown to be downregulated in breast cancers, suggesting that
dysregulation of these kinases contributes to breast cancer pathology. In this proposal, we aim to use genetic
mouse models and ex vivo analysis of primary cells to define how loss of LATS1/2 contributes to the
pathogenesis of breast cancer. We have shown that in the homeostatic mammary gland, luminal epithelial cells
exhibit active LATS1/2, with restricted YAP/TAZ activity. Our data demonstrate that conditional deletion of
LATS1/2 in the luminal mammary epithelium leads to the rapid proliferation of a population of cells within the
mammary duct. Notably, expanded cells display traits associated with luminal progenitors, a proposed cell of
origin of basal-like and triple-negative breast cancers. Through lineage tracing, our data suggest that the
proliferating lesions are comprised of a heterogeneous mixture of LATS1/2-null and LATS1/2-WT cells, and
exhibit significant nuclear localization of YAP/TAZ. Furthermore, LATS1/2-null cells derived from our mice are
capable of forming tumors when injected subcutaneously into wild-type mice. Our goals in this proposal are to:
1) define how loss of LATS1/2 affects mammary gland homeostasis and contributes to the development of
invasive carcinoma through the activity of YAP/TAZ; and 2) identify potential therapeutic targets for LATS1/2-
null mammary carcinomas using transcriptional profiling. Collectively, our proposed studies will provide crucial
insight into the molecular aberrations underlying the development of breast cancer, which we hope will lead to
more impactful treatments and diagnostic strategies for this disease in the future.

## Key facts

- **NIH application ID:** 10226138
- **Project number:** 5F31CA232683-04
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Joseph Kern
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226138

## Citation

> US National Institutes of Health, RePORTER application 10226138, Determining the roles of the Hippo pathway kinases LATS1 and LATS2 in mammary gland homeostasis and disease (5F31CA232683-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10226138. Licensed CC0.

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