# Role of LSD1 in Triple Negative Breast Cancer Development and Therapeutic Response

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $332,124

## Abstract

PROJECT SUMMARY/ABSTRACT
Breast cancer (BC) is the most common cancer and the second leading cause of cancer death in American
women. About 10-20% of breast cancers are triple-negative breast cancer (TNBC), which has a propensity to
metastasize, recur, and develop resistance to chemotherapy. TNBC is the only subtype of BC for which there is
no targeted therapy. Chemotherapies remain the mainstay of treatment for TNBC, but their clinical efficacy is
often limited by resistance. Immunotherapy is emerging as an exciting new treatment option for TNBC patients.
While TNBC is more likely to respond to immunotherapy, overall response rate is still low. Developing novel and
more effective TNBC therapies is an unmet biomedical need as most of advanced TNBCs do not respond well
to current therapies. Epigenetic alterations such as DNA hypermethylation and histone dysregulation have been
associated with all stages of TNBC formation and progression. Lysine-specific demethylase 1 (LSD1) is the first
identified histone demethylase which specifically demethylates H3K4me1/2. LSD1 is a key component of multiple
transcription repressor complexes. Tumors in TNBC patients frequently express higher level of LSD1 compared
to other BC groups. Clinically, LSD1 protein overexpression is significantly associated with worse prognosis in
TNBC patients, making it an attractive therapeutic target. Our recent study has revealed a new mechanism
driving LSD1 protein overexpression in TNBC through HDAC5-mediated posttranslational modification.
Treatment with LSD1 inhibitors effectively suppresses tumor progression and sensitizes TNBC cells to
chemotherapeutic agents. Furthermore, LSD1 ablation stimulates antitumor immunity and potentiates the
efficacy of anti-PD-1 antibody in poorly immunogenic TNBC. LSD1 inhibition leads to reexpression of a key
epigenetically silenced tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), which is required for
tumor suppression and responsiveness to immunotherapy. Based on these findings, we hypothesize that LSD1
overexpression facilitates TNBC development and inhibition of LSD1 improves TNBC therapies by inducing
TFPI2-mediated cell killing and antitumor immunity. Aim1. Determine the functional roles of LSD1
overexpression in TNBC development; Aim2. Evaluate the in vitro and in vivo therapeutic efficacy of LSD1
inhibition against TNBC; Aim3. Elucidate the immunogenic effects of LSD1 inhibition in TNBC. The results from
the proposed studies are expected to provide new mechanistic insights and key preclinical evidence for using
LSD1 inhibitors in TNBC. In the long run, these studies may lead to new and improved therapies for patients
with relapsed and refractory TNBC.

## Key facts

- **NIH application ID:** 10795658
- **Project number:** 5R01CA260357-05
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Yi Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $332,124
- **Award type:** 5
- **Project period:** 2023-08-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795658

## Citation

> US National Institutes of Health, RePORTER application 10795658, Role of LSD1 in Triple Negative Breast Cancer Development and Therapeutic Response (5R01CA260357-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10795658. Licensed CC0.

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