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Tumor suppressor function of Syk in human MCF10A in vitro and normal mouse mammary epithelium in vivo.

ABSTRACT: The normal function of Syk in epithelium of the developing or adult breast is not known, however, Syk suppresses tumor growth, invasion, and metastasis in breast cancer cells. Here, we demonstrate that in the mouse mammary gland, loss of one Syk allele profoundly increases proliferation and ductal branching and invasion of epithelial cells through the mammary fat pad during puberty. Mammary carcinomas develop by one year. Syk also suppresses proliferation and invasion in vitro. siRNA or shRNA knockdown of Syk in MCF10A breast epithelial cells dramatically increased proliferation, anchorage independent growth, cellular motility, and invasion, with formation of functional, extracellular matrix-degrading invadopodia. Morphological and gene microarray analysis following Syk knockdown revealed a loss of luminal and differentiated epithelial features with epithelial to mesenchymal transition and a gain in invadopodial cell surface markers CD44, CD49F, and MMP14. These results support the role of Syk in limiting proliferation and invasion of epithelial cells during normal morphogenesis, and emphasize the critical role of Syk as a tumor suppressor for breast cancer. The question of breast cancer risk following systemic anti-Syk therapy is raised since only partial loss of Syk was sufficient to induce mammary carcinomas.

SUBMITTER: Sung YM

PROVIDER: S-EPMC2759536 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Tumor suppressor function of Syk in human MCF10A in vitro and normal mouse mammary epithelium in vivo.

Sung You Me YM Xu Xuehua X Sun Junfeng J Mueller Duane D Sentissi Kinza K Johnson Peter P Urbach Elana E Seillier-Moiseiwitsch Françoise F Johnson Michael D MD Mueller Susette C SC

PloS one 20091015 10

The normal function of Syk in epithelium of the developing or adult breast is not known, however, Syk suppresses tumor growth, invasion, and metastasis in breast cancer cells. Here, we demonstrate that in the mouse mammary gland, loss of one Syk allele profoundly increases proliferation and ductal branching and invasion of epithelial cells through the mammary fat pad during puberty. Mammary carcinomas develop by one year. Syk also suppresses proliferation and invasion in vitro. siRNA or shRNA kn ...[more]

PMID: 19829710

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Project description:Since the advent of screening mammography, approximately one-quarter of newly diagnosed breast cancers are at the earliest preinvasive stage of ductal carcinoma in situ (DCIS). Concomitant with this improvement in early detection has been a growing clinical concern that distinguishing aggressive from indolent DCIS is necessary to optimize patient management. Genetically engineered mouse models offer an appealing experimental framework in which to investigate factors that influence and predict progression of preinvasive neoplasias. Because of the small size of early stage carcinomas in mice, high-resolution imaging techniques are required to effectively observe longitudinal progression. The purpose of the present study was to evaluate the feasibility of MRI for assessment of in situ mammary neoplasias and early invasive mammary cancers that stochastically arise in mammary glands of C3(1) SV40 Tag transgenic mice. Additionally, images of normal mammary glands from wild-type FVB/N mice were acquired and compared with those from transgenic mice. Sixteen mice underwent MR examinations employing axial two-dimensional multi-slice gradient recalled echo scans (TR/TE =∼1000/5.5 ms) with fat suppression in a two-step process targeting both the upper and lower mammary glands. MRI successfully detected in situ and early invasive neoplasias in transgenic mice with high sensitivity and specificity. The average signal-to-noise ratio (SNR) of in situ lesions on fat-suppressed high-resolution T(1) -weighted images was 22.9, which was lower than that of invasive tumors, lymph nodes and muscle (average SNR of 29.5-34.9, p < 0.0001) but significantly higher than that of normal mammary tissue (average SNR = 5.5, p < 0.0001). Evaluation of wild-type mammary glands revealed no cancerous or benign lesions, and comparable image contrast characteristics (average SNR = 5.2) as compared with normal tissue areas of transgenic mice. This present study demonstrates that MRI is an excellent candidate for performing longitudinal assessment of early stage mammary cancer disease progression and response to therapy in the transgenic model system.

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Dataset Information

Tumor suppressor function of Syk in human MCF10A in vitro and normal mouse mammary epithelium in vivo.

Publications

Tumor suppressor function of Syk in human MCF10A in vitro and normal mouse mammary epithelium in vivo.

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