Quantitative analysis of three-dimensional human mammary epithelial tissue architecture reveals a role for tenascin-C in regulating c-met function

Agne Taraseviciute, Benjamin T. Vincent, Pepper Schedin, Peter Lloyd Jones

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Remodeling of the stromal extracellular matrix and elevated expression of specific proto-oncogenes within the adjacent epithelium represent cardinal features of breast cancer, yet how these events become integrated is not fully understood. To address this question, we focused on tenascin-C (TN-C), a stromal extracellular matrix glycoprotein whose expression increases with disease severity. Initially, nonmalignant human mammary epithelial cells (MCF-10A) were cultured within a reconstituted basement membrane (BM) where they formed three-dimensional (3-D) polarized, growth-attenuated, multicellular acini, enveloped by a continuous endogenous BM. In the presence of TN-C, however, acini failed to generate a normal BM, and net epithelial cell proliferation increased. To quantify how TN-C alters 3-D tissue architecture and function, we developed a computational image analysis algorithm, which showed that although TN-C disrupted acinar surface structure, it had no effect on their volume. Thus, TN-C promoted epithelial cell proliferation leading to luminal filling, a process that we hypothesized involved c-met, a proto-oncogene amplified in breast tumors that promotes intraluminal filling. Indeed, TN-C increased epithelial c-met expression and promoted luminal filling, whereas blockade of c-met function reversed this phenotype, resulting in normal BM deposition, proper lumen formation, and decreased cell proliferation. Collectively, these studies, combining a novel quantitative image analysis tool with 3-D organotypic cultures, demonstrate that stromal changes associated with breast cancer can control proto-oncogene function.

Original languageEnglish (US)
Pages (from-to)827-838
Number of pages12
JournalAmerican Journal of Pathology
Volume176
Issue number2
DOIs
StatePublished - Feb 2010
Externally publishedYes

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Tenascin
Human Mammary Glands
Basement Membrane
Proto-Oncogenes
Epithelial Cells
Cell Proliferation
Breast Neoplasms
Extracellular Matrix
Glycoproteins
Breast
Epithelium
Phenotype
Growth

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Quantitative analysis of three-dimensional human mammary epithelial tissue architecture reveals a role for tenascin-C in regulating c-met function. / Taraseviciute, Agne; Vincent, Benjamin T.; Schedin, Pepper; Jones, Peter Lloyd.

In: American Journal of Pathology, Vol. 176, No. 2, 02.2010, p. 827-838.

Research output: Contribution to journalArticle

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