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Nectin-4 and p95-ErbB2 cooperatively regulate Hippo signaling-dependent SOX2 gene expression, enhancing

Shin Kedashiro1, Takeshi Kameyama1, Kiyohito Mizutani2

  • 1Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.

Scientific Reports
|April 2, 2021
PubMed

Insights

Nectin-4 and p95-ErbB2 enhance breast cancer cell proliferation in suspension by upregulating SOX2 gene expression via Hippo signaling. This interaction is crucial for anchorage-independent growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Nectin-4 is upregulated in cancer cells and interacts with ErbB2 variants.
  • Trastuzumab resistance is a significant challenge in ErbB2-positive breast cancer.
  • The role of nectin-4 in cancer cell proliferation, especially in anchorage-independent conditions, requires further elucidation.

Purpose of the Study:

  • To investigate the cooperative effects of nectin-4 and ErbB2 variants on SOX2 gene expression and cell proliferation in suspension culture.
  • To elucidate the signaling pathways, including PI3K-AKT and Hippo signaling, involved in nectin-4 and p95-ErbB2-mediated cell growth.
  • To determine the specific interaction between nectin-4 and p95-ErbB2 that drives SOX2 gene expression and anchorage-independent proliferation.

Main Methods:

  • Utilized T47D human breast cancer cells in suspension culture.
  • Assessed nectin-4 and ErbB2 variant interactions (p95-ErbB2, ErbB2, ErbB2∆Ex16).
  • Measured SOX2 gene expression, PI3K-AKT signaling activation, Hippo signaling pathway activity, and YAP regulation.
  • Evaluated cell proliferation and anchorage-independent growth.

Main Results:

  • Nectin-4 and p95-ErbB2, but not nectin-4 with ErbB2 or ErbB2∆Ex16, cooperatively enhanced SOX2 gene expression and proliferation in suspension.
  • Both nectin-4/ErbB2 variants activated PI3K-AKT signaling similarly, but only nectin-4/p95-ErbB2 enhanced SOX2 expression.
  • Nectin-4 and p95-ErbB2 uniquely activated Hippo signaling, leading to YAP inactivation and increased SOX2 expression, driving anchorage-independent proliferation.

Conclusions:

  • The combination of nectin-4 and p95-ErbB2 specifically regulates Hippo signaling-dependent SOX2 gene expression.
  • This interaction is critical for enhancing anchorage-independent proliferation of T47D breast cancer cells.
  • Targeting the nectin-4/p95-ErbB2 interaction may offer a therapeutic strategy for trastuzumab-resistant breast cancer.

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