Gene signatures of inflammatory breast cancer: Epithelial plasticity and a cancer stem cell phenotype

Fredika M. Robertson*, Khoi Chu, Sandra V. Fernandez, Zaiming Ye, Sanford H. Barsky, Massimo Cristofanilli

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Inflammatory breast cancer (IBC) is the most lethal variant of locally advanced breast cancer and carries with it a very low survival rate of 40 % at 5 years. IBC does not present as a lump but rather mimics characteristics of an inflammation that first appears as swelling of the breast, with edema, redness, and common lymph node involvement. The physical changes in the breast are associated with the presence of nests of aggregated tumor cells, defined as tumor emboli that are encircled by lymphatic vessels, effectively blocking lymphatic drainage. Little is understood about IBC, in part due to the lack of preclinical models that recapitulate its distinct characteristics. This chapter provides an overview of our studies that have profiled all available preclinical models of IBC, including two new models recently developed, to elucidate the molecular underpinnings of this lethal variant of breast cancer. Our studies demonstrate that IBC is enriched for cells that express CD44+ and CD133+ and have aldehyde dehydrogenase-1 (ALDH1) activity, supporting a cancer stem cell/tumor initiating phenotype, associated with a very high metastatic potential to multiple distant organ sites. IBC has a distinct gene signature including E-cadherin expression with associated loss of expression of ZEB1, a transcriptional repressor of E-cadherin. IBC is also characterized by loss of expression of genes within the transforming growth factor-beta (TGFβ) signaling pathway, which is permissive for cohesive invasion by IBC tumor emboli. Taken together, these studies suggest that IBC is a very distinct variant of breast cancer characterized by epithelial plasticity, enrichment of a stem cell phenotype, and cohesive invasion as an adaptive survival mechanism, consistent with the definition of IBC as the most metastatic variant of breast cancer.

Original languageEnglish (US)
Title of host publicationCell and Molecular Biology of Breast Cancer
PublisherHumana Press Inc
Pages305-322
Number of pages18
ISBN (Electronic)9781627036344
ISBN (Print)1627036334, 9781627036337
DOIs
StatePublished - Jun 1 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Robertson, F. M., Chu, K., Fernandez, S. V., Ye, Z., Barsky, S. H., & Cristofanilli, M. (2013). Gene signatures of inflammatory breast cancer: Epithelial plasticity and a cancer stem cell phenotype. In Cell and Molecular Biology of Breast Cancer (pp. 305-322). Humana Press Inc. https://doi.org/10.1007/978-1-62703-634-4_14