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A Modified In vitro Invasion Assay to Determine the Potential Role of Hormones, Cytokines and/or Growth Factors in Mediating Cancer Cell Invasion
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Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential

Sreeharsha Gurrapu1, Emanuela Pupo2, Giulia Franzolin1,3

  • 1Cancer Cell Biology Laboratory, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy.

Cell Death and Differentiation
|March 21, 2018
PubMed

Insights

Semaphorin 4C (Sema4C) signaling drives breast cancer growth and metastasis. Inhibiting Sema4C or its receptor PlexinB2 halts tumor cell proliferation and invasiveness, revealing a potential therapeutic target.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Signaling

Background:

  • Semaphorin 4C (Sema4C) expression is linked to poor outcomes in human breast cancers.
  • The role of Sema4C in breast cancer progression, particularly in luminal-type cancers, requires further elucidation.

Purpose of the Study:

  • To investigate the functional role of Semaphorin 4C (Sema4C) and its receptor PlexinB2 in breast cancer cell growth, phenotype, and metastasis.
  • To identify the underlying molecular mechanisms of Sema4C/PlexinB2 signaling in breast carcinoma.

Main Methods:

  • Knock-down experiments of Sema4C and PlexinB2 in mammary carcinoma cell lines.
  • Analysis of cell cycle progression, cytokinesis, and senescence.
  • Investigation of RhoA-GTP levels and downstream signaling pathways.
  • Assessment of phenotypic changes including cell polarity, migration, and invasiveness.
  • In vivo studies using mouse models of estrogen-independent metastatic tumors.

Main Results:

  • Sema4C/PlexinB2 signaling is crucial for maintaining RhoA-GTP levels, essential for cancer cell proliferation.
  • Inhibition of Sema4C/PlexinB2 leads to growth arrest, cell cycle defects, and senescence in carcinoma cells.
  • Sema4C upregulation induces phenotypic changes promoting invasiveness and metastasis, including altered cell polarity and increased transcription factors like Snail, Slug, and SOX-2.
  • Sema4C-overexpressing cells form estrogen-independent metastatic tumors in vivo.
  • The signaling cascade involves ErbB2 and RhoA-dependent kinases.

Conclusions:

  • Sema4C/PlexinB2 signaling is a critical driver of breast carcinoma cell growth and represents a novel therapeutic target.
  • Elevated Sema4C expression promotes the transition of indolent luminal breast cancers to an aggressive, metastatic phenotype, potentially explaining its association with poor prognosis.

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