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<p>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 <i>MUC1</i> 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 <i>ESR1</i> 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.</p>

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MUC1-C dependency in drug resistant HR+/HER2− breast cancer identifies a new target for antibody-drug conjugate treatment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月26日

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  • Ayako Nakashoji,
  • Atrayee Bhattacharya,
  • Hiroki Ozawa,
  • Naoki Haratake,
  • Keisuke Shigeta,
  • Atsushi Fushimi,
  • Nami Yamashita,
  • Akira Matsui,
  • Shoko Kure,
  • Tomoe Kameyama,
  • Makoto Takeuchi,
  • Kazumasa Fukuda,
  • Takamichi Yokoe,
  • Aiko Nagayama,
  • Tetsu Hayahsida,
  • Yuko Kitagawa,
  • Renyan Liu,
  • Antonio Giordano,
  • Rinath Jeselsohn,
  • Geoffrey I. Shapiro,
  • Donald Kufe

摘要

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.