SNAIL is induced by tamoxifen and leads to growth inhibition in invasive lobular breast carcinoma

Breast Cancer Res Treat. 2019 Jun;175(2):327-337. doi: 10.1007/s10549-019-05161-8. Epub 2019 Feb 23.


Purpose: Invasive lobular carcinoma (ILC) is a histological subtype of breast cancer that is predominantly estrogen receptor alpha (ER)-positive (+) and is thus treated with endocrine therapies. Herein, we sought to understand the molecular underpinnings of the 4-hydroxytamoxifen (4OHT) resistance in ILC by assessing the potential role of the epithelial-to-mesenchymal transition transcription factor (EMT-TF) SNAIL (SNAI1).

Methods: Using a series of breast cancer cell lines, we measured the basal, estrogen and 4OHT-induced expression of SNAIL and other EMT-TF family members by quantitative reverse transcription-polymerase chain reaction and immunoblotting. Chromatin immunoprecipitation experiments were performed to assess ER binding to the SNAIL promoter. Cell proliferation, cell cycle and apoptosis were assessed in 2D cultures. 3D growth was assessed in Matrigel and Collagen I cultures.

Results: Estrogen and 4OHT induced SNAIL expression, but not that of the other EMT-TF family members SLUG (SNAI2) and SMUC (SNAI3), with the 4OHT effect being specific to the lobular but not the ductal subtype. We observed estrogen and 4OHT-induced ER recruitment to the SNAI1 promoter and high endogenous basal levels of SNAIL and several EMT-TFs in ILC cell lines. While SNAIL knockdown had a minor impact on the 4OHT partial agonism in estrogen-depleted conditions, it led to a surprising increase in cell proliferation in full serum. In complementary experiments, inducible SNAI1 overexpression caused decreased proliferation, associated with a cell cycle arrest in G0/G1. Additionally, apoptosis was observed in BCK4 cells.

Conclusion: These data suggest a previously unrecognized role for SNAIL in ILC, substantiating a context-dependent behavior for this EMT-TF.

Keywords: Breast cancer; EMT; ER; Lobular; SNAIL; Tamoxifen.

MeSH terms

  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Carcinoma, Lobular / drug therapy*
  • Carcinoma, Lobular / genetics
  • Carcinoma, Lobular / pathology
  • Cell Cycle Checkpoints / drug effects
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Epithelial-Mesenchymal Transition / genetics
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • MCF-7 Cells
  • Neoplasm Invasiveness / genetics*
  • Neoplasm Invasiveness / pathology
  • Signal Transduction / drug effects
  • Snail Family Transcription Factors / genetics*
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology


  • Estrogen Receptor alpha
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • Tamoxifen
  • afimoxifene
  • Estradiol