# Non-canonical roles of Mitotic Arrest Deficient 1 (Mad1) in tumor promotion

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $446,389

## Abstract

Breast cancer is the most commonly diagnosed malignancy in women worldwide. Mitotic Arrest Deficient 1
(Mad1) is commonly upregulated in breast cancer where it serves as a marker of poor prognosis, and
upregulation of Mad1 is sufficient for tumorigenesis in orthotopic breast cancer models. Mad1 was identified and
characterized for its function in mitosis, where it serves to prevent chromosome missegregation/chromosomal
instability (CIN). CIN has been implicated in promoting both primary and metastatic tumors. However, Mad1 is
expressed throughout interphase and we have recently shown that a non-canonical interphase function of Mad1
in destabilizing the p53 tumor suppressor is critical for Mad1 upregulation to promote orthotopic mammary tumor
growth. Additionally, we identified a previously unrecognized pool of Mad1 that localizes to the Golgi apparatus.
At the Golgi, Mad1 performs another non-canonical function in the maturation and secretion of newly synthesized
α5 integrin, a critical metastasis promoter and marker of poor prognosis. Thus, Mad1 upregulation results in
three tumor- and metastasis-promoting phenotypes: CIN, p53 destabilization and α5 integrin secretion. Aim 1
will determine which functions of Mad1 upregulation are necessary and sufficient for tumor promotion using
separation of function mutants, competition experiments, specific inhibitors, and novel CRISPR/Cas9 edited
mouse models. Aim 2 will define the mechanisms by which Mad1 functions in the secretion of newly synthesized
α5 integrin, which will provide novel opportunities to inhibit α5 integrin activity in promoting metastasis. Together,
the proposed experiments will identify the mechanistic basis of the tumor promoting activity of Mad1 and define
the α5 integrin biosynthetic trafficking pathway, which will expand our fundamental understanding of breast
cancer and reveal novel therapeutic targets.

## Key facts

- **NIH application ID:** 10828786
- **Project number:** 5R01CA270133-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Beth A Weaver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $446,389
- **Award type:** 5
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828786

## Citation

> US National Institutes of Health, RePORTER application 10828786, Non-canonical roles of Mitotic Arrest Deficient 1 (Mad1) in tumor promotion (5R01CA270133-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10828786. Licensed CC0.

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