# Role of CCN6 (WISP3) in the progression and metastasis of breast cancer

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $363,090

## Abstract

Metaplastic breast carcinomas (mBrCAs) are a subset of triple negative breast cancer (TNBC) that occurs
with higher frequency in African and African-American (AA) women, have histological evidence of
epithelial-to-mesenchymal transition (EMT), and poor prognosis compared with other TNBC. mBrCAs
consisting of spindle cells are the most frequent and the most lethal subtype. In humans TP53 is mutated
with similar frequency in mBrCAs and in non-metaplastic TNBC (60-80% of cases). At present, the defining
molecular alterations of mBrCAs are far from understood, and the 5-year overall survival for patients with
mBrCA is 54% compared to 73% for TNBC. Our lab has discovered that CCN6 protein is reduced in 68%
of human mBrCAs compared to 33% of other breast cancer types (p<0.02). A major breakthrough in our
lab during the previous cycle has been the generation of a mammary epithelial cell-specific Ccn6 knockout
mouse model that demonstrates a tumor suppressor function for Ccn6 in mBrCAs. All mammary tumors in
MMTV-Cre;Ccn6fl/fl mice resemble human spindle mBrCAs morphologically and at the transcriptional level,
and they share increased nuclear localization of beta-catenin in 78% of tumors, and increased expression
of the canonical Wnt target genes HMGA2 and IMP2 (IGF2BP2). Since the initial submission, we have
discovered that extracellular CCN6 antagonizes the effect of Wnt ligands on beta-catenin activation in vivo
and in vitro, but the mechanisms, cooperating events, and functional consequences need further
investigation. Our CENTRAL HYPOTHESIS is that loss of CCN6 expression is required to drive spindle
mBrCAs, at least in part by enhancing Wnt/beta-catenin mediated activation of pro-invasive and pro-
metastatic targets, such as HMGA2 and IMP2, and that detection of CCN6, beta-catenin, HMGA2, and
IMP2 proteins may serve as specific biomarkers of mBrCA in clinical tissue samples, with diagnostic and
treatment utility. We propose three independent and complementary specific aims: AIM 1. To investigate
the consequences of inducible mammary epithelial cell-specific Ccn6 knockout as a driver of the unique
spindle mBrCA phenotype, and to investigate the cooperation with p53. AIM 2. To elucidate the molecular
mechanism(s) by which CCN6 suppresses progression of spindle mBrCAs in vivo and in vitro. AIM 3. To
evaluate the translational impact of CCN6, beta-catenin, HMGA2, and IMP2 in breast tissue samples of
African, AA, and Whites. We have developed a unique mouse model and have characterized cohorts of
human breast cancer tissues (n>4,000, including 200 from Ghanaian, and 275 cases of mBrCAs of all
races) with clinical information and >15 years of follow-up. We have generated critical preliminary data,
which provide a strong scientific premise. The reagents and expertise are in place in the PI and co-
Investigator's laboratories. Our innovative studies are expected to provide insights into new diagnostic
markers and therapeutic targets for this aggressive sub...

## Key facts

- **NIH application ID:** 10447058
- **Project number:** 5R01CA125577-14
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Celina G Kleer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $363,090
- **Award type:** 5
- **Project period:** 2008-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447058

## Citation

> US National Institutes of Health, RePORTER application 10447058, Role of CCN6 (WISP3) in the progression and metastasis of breast cancer (5R01CA125577-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10447058. Licensed CC0.

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