# Cytokeratin 5/Beta-catenin interaction and crosstalk in hormone regulated breast cancer stem cells

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2020 · $34,850

## Abstract

Project Summary
Breast cancer is the second-leading cause of cancer-related deaths in women. Over two thirds of breast
cancers are estrogen receptor (ER) and progesterone receptor (PR) positive (termed luminal), and account for
the majority of breast cancer deaths. Following endocrine treatments, residual luminal breast cancer cells can
become dormant and pose a risk of recurrence that can last up to 20 years. The existence of a rare population
of cancer stem cells (CSCs) that are more quiescent, self-renewing, invasive, drug resistant, and tumor
initiating than non-CSCs may explain the prolonged risk of recurrence in luminal breast cancer. Our laboratory
has previously identified the intermediate filament protein cytokeratin 5 (CK5) as a marker of luminal breast
CSCs. These cells are relatively rare in luminal breast cancers but can be expanded by progesterone or
estrogen deprivation. CK5 knockdown, knockout, and overexpression in luminal breast cancer cell lines has
indicated that CK5 is both necessary and sufficient, respectively, for mammosphere formation, a measurement
of cancer cell self-renewal. This suggests that CK5 may have a functional role in maintaining a luminal breast
CSC population, but how it accomplishes this is still unknown. Although cytokeratins are largely regarded as
structural proteins that protect epithelial cells from stress, recent studies have identified that cytokeratins affect
cell signaling through protein-protein interactions. We performed an unbiased immunoprecipitation (IP)-mass
spectrometry screen to identify novel CK5 interacting proteins in luminal breast cancer cells. We identified β-
catenin, the key transcription factor of the Wnt signaling pathway and essential component of adherens
junctions, as an interactor of CK5 and confirmed this interaction in luminal and basal breast cancer cell lines
and a PDX model. We found that in addition to increasing mammosphere formation and CK5 expression,
progesterone was capable of increasing β-catenin transcriptional activity, which was abrogated by CK5
CRISPR knockout. Furthermore, both CK5 overexpression and progesterone treatment caused loss of
membrane β-catenin which could have implications in the invasive potential of these cells. Several members of
the 14-3-3 family of scaffolding proteins were identified by IP-MS and confirmed by co-IP. These proteins are
known to interact with β-catenin. Therefore, this proposal tests the hypothesis that progesterone induced CK5+
CSCs rely on altered β-catenin dynamics mediated by 14-3-3 proteins to promote luminal breast tumor
progression. The specific aims of this proposal are to 1) evaluate the dependence of progesterone induced
CSCs on CK5 and β-catenin dynamics, and 2) determine if the CK5/14-3-3 interaction is necessary for altered
β-catenin dynamics. These studies will define novel protein interactions that contribute to luminal breast CSC
maintenance, which could ultimately lead to development of new strategies to preve...

## Key facts

- **NIH application ID:** 9879624
- **Project number:** 5F31CA232456-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Olivia F McGinn
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $34,850
- **Award type:** 5
- **Project period:** 2019-02-20 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879624

## Citation

> US National Institutes of Health, RePORTER application 9879624, Cytokeratin 5/Beta-catenin interaction and crosstalk in hormone regulated breast cancer stem cells (5F31CA232456-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9879624. Licensed CC0.

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