Immutable functional attributes of histologic grade revealed by context-independent gene expression in primary breast cancer cells.
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.
California Pacific Medical Center Research Institute, San Francisco, California, CA 94107, USA.
Shanaz H
SH
Dairkee
Aejaz
A
Sayeed
Gloria
G
Luciani
Stacey
S
Champion
Zhenhang
Z
Meng
Lakshmi R
LR
Jakkula
Heidi S
HS
Feiler
Joe W
JW
Gray
Dan H
DH
Moore
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D002135:Calcium-Binding Proteins; D009363:Neoplasm Proteins; C103003:S100P protein, human