MUC1-C dependency in drug resistant HR+/HER2− breast cancer identifies a new target for antibody-drug conjugate treatment
Treatment of hormone receptor (HR)-positive, HER2-negative breast cancer (HR+/HER2- BC) is limited by resistance to endocrine therapy (ET) and CDK4/6 inhibitors. There is no known common pathway that confers resistance to these agents. We report that (i) the MUC1 gene is upregulated in HR+/HER2- BCs and (ii) the MUC1-C protein regulates estrogen receptor alpha (ER)-driven transcriptomes. Mechanistically, we demonstrate that MUC1-C is necessary for expression of SRC-3 and MED1 coactivators that drive ER-mediated target gene transcription. Cells with ESR1 mutations that confer ET resistance, as well as cells with acquired resistance to the CDK4/6 inhibitor abemaciclib, are dependent on MUC1-C for (i) expression of these coactivators and ER target genes, (ii) survival, and (iii) self-renewal capacity. In support of these results, we show that treatment of HR+/HER2- BC cells with an anti-MUC1-C antibody-drug conjugate (ADC) effectively inhibits survival, self-renewal and tumorgenicity. These findings indicate that MUC1-C is a common effector of drug-resistant HR+/HER2- BC cells and is a potential target for their treatment.
Authors
- Tomoe Kameyama
- Kazumasa Fukuda (ORCID: https://orcid.org/0000-0001-6126-6118)
- Makoto Takeuchi (ORCID: https://orcid.org/0000-0002-2516-2044)
- Atrayee Bhattacharya (ORCID: https://orcid.org/0000-0002-3322-6175)
- Atsushi Fushimi (ORCID: https://orcid.org/0000-0003-1328-8835)
- Keisuke Shigeta (ORCID: https://orcid.org/0000-0002-9405-9446)
- Shoko Kure (ORCID: https://orcid.org/0000-0002-9536-9438)
- Geoffrey Ira Shapiro (ORCID: https://orcid.org/0000-0002-3331-4095)
- Takamichi Yokoe (ORCID: https://orcid.org/0000-0001-7068-7117)
- Rinath M. Jeselsohn (ORCID: https://orcid.org/0000-0001-7996-7529)
- Aiko Nagayama (ORCID: https://orcid.org/0000-0002-7453-8132)
- Donald Küfe (ORCID: https://orcid.org/0000-0001-5743-8888)
- Hiroki Ozawa (ORCID: https://orcid.org/0000-0002-3771-7940)
- Nami Yamashita (ORCID: https://orcid.org/0000-0001-7182-1090)
- Akira Matsui (ORCID: https://orcid.org/0000-0002-0174-914X)
- Naoki Haratake (ORCID: https://orcid.org/0000-0002-3098-4798)
- Ayako Nakashoji (ORCID: https://orcid.org/0000-0003-2443-6995)
- Antonio Giordano (ORCID: https://orcid.org/0000-0002-7760-9717)
- Renyan Liu (ORCID: https://orcid.org/0009-0009-5676-3350)
- Yuko Kitagawa
- Tetsu Hayahsida
Institutions
- Harvard University (US)
- Keio University (JP)
- Tokyo Medical Center (JP)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
- National Hospital Organization (JP)
Publication Details
- Journal
- npj Breast Cancer
- Published
- 2025-04-26
- DOI
- https://doi.org/10.1038/s41523-025-00751-w
- Citations
- 5
- Primary Topic
- Advanced Breast Cancer Therapies
- Type
- article
- Field-Weighted Citation Impact
- 7.59
Funders
- National Institutes of Health
- National Cancer Institute