Immutable functional attributes of histologic grade revealed by context-independent gene expression in primary breast cancer cells

Shanaz H. Dairkee, Aejaz Sayeed, Gloria Luciani, Stacey Champion, Meng Zhenhang, Lakshmi R. Jakkula, Heidi Feiler, Joe Gray, Dan H. Moore

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Inherent cancer phenotypes that are independent of fluctuating cross-talk with the surrounding tissue matrix are highly desirable candidates for targeting tumor cells. Our novel study design uses epithelial cell lines derived from low versus high histologic grade primary breast cancer to effectively diminish the breadth of transient variability generated within the tumor microenvironment of the host, revealing a "paracrine-independent expression of grade-associated" (PEGA) gene signature. PEGA members extended beyond "proliferation-driven" signatures commonly associated with aggressive, high-grade breast cancer. The calcium-binding protein S100P was prominent among PEGA genes overexpressed in high-grade tumors. A three-member fingerprint of S100P-correlated genes, consisting of GPRC5A, FXYD3, and PYCARD, conferred poor outcome in multiple breast cancer data sets, irrespective of estrogen receptor status but dependent on tumor size (P <0.01). S100P silencing markedly diminished coregulated gene transcripts and reversed aggressive tumor behavior. Exposure to pathway-implicated agents, including the calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, phenothiazine, and chlorpromazine, resulted in rapid apoptotic cell death in high-grade tumor cells resistant to the chemotherapeutic drug cisplatin. This is the first comprehensive study describing molecular phenotypes intimately associated with histologic grade whose expression remains relatively fixed despite an unavoidably changing environment to which tumor cells are invariably exposed.

Original languageEnglish (US)
Pages (from-to)7826-7834
Number of pages9
JournalCancer Research
Volume69
Issue number19
DOIs
StatePublished - Oct 1 2009
Externally publishedYes

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Breast Neoplasms
Gene Expression
Neoplasms
Genes
Phenotype
Calcium-Binding Proteins
Tumor Microenvironment
Chlorpromazine
Dermatoglyphics
Calmodulin
Estrogen Receptors
Cisplatin
Cell Death
Epithelial Cells
Cell Line
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dairkee, S. H., Sayeed, A., Luciani, G., Champion, S., Zhenhang, M., Jakkula, L. R., ... Moore, D. H. (2009). Immutable functional attributes of histologic grade revealed by context-independent gene expression in primary breast cancer cells. Cancer Research, 69(19), 7826-7834. https://doi.org/10.1158/0008-5472.CAN-09-1564

Immutable functional attributes of histologic grade revealed by context-independent gene expression in primary breast cancer cells. / Dairkee, Shanaz H.; Sayeed, Aejaz; Luciani, Gloria; Champion, Stacey; Zhenhang, Meng; Jakkula, Lakshmi R.; Feiler, Heidi; Gray, Joe; Moore, Dan H.

In: Cancer Research, Vol. 69, No. 19, 01.10.2009, p. 7826-7834.

Research output: Contribution to journalArticle

Dairkee, Shanaz H. ; Sayeed, Aejaz ; Luciani, Gloria ; Champion, Stacey ; Zhenhang, Meng ; Jakkula, Lakshmi R. ; Feiler, Heidi ; Gray, Joe ; Moore, Dan H. / Immutable functional attributes of histologic grade revealed by context-independent gene expression in primary breast cancer cells. In: Cancer Research. 2009 ; Vol. 69, No. 19. pp. 7826-7834.
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