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N-cadherin regulates mammary tumor cell migration through Akt3 suppression.

ABSTRACT: N-cadherin is a cell-cell adhesion molecule that plays a role in breast cancer metastasis. Here, we show that in vivo expression of N-cadherin in the PyMT mouse model, which enhances mammary tumor metastasis, results in selective inhibition of Akt3 expression and phosphorylation. Similarly, exogenous expression of N-cadherin in PyMT or MCF-7 mammary tumor cells enhanced cell motility and caused a dramatic reduction in Akt3 expression and phosphorylation. Moreover, knockdown of Akt3 in PyMT tumor cells increased cell motility and disrupted mammary morphogenesis, but had no effect on cell proliferation. Conversely, overexpression of wild-type Akt3 in PyMT-N-cadherin cells inhibited cell motility promoted by N-cadherin. Taken altogether, these findings demonstrate that N-cadherin suppresses Akt3 to promote cell motility and highlight the intricate regulation of Akt isoforms by N-cadherin during metastasis.

SUBMITTER: Chung S

PROVIDER: S-EPMC4351658 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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N-cadherin regulates mammary tumor cell migration through Akt3 suppression.

Chung S S Yao J J Suyama K K Bajaj S S Qian X X Loudig O D OD Eugenin E A EA Phillips G R GR Hazan R B RB

Oncogene 20120312 4

N-cadherin is a cell-cell adhesion molecule that plays a role in breast cancer metastasis. Here, we show that in vivo expression of N-cadherin in the PyMT mouse model, which enhances mammary tumor metastasis, results in selective inhibition of Akt3 expression and phosphorylation. Similarly, exogenous expression of N-cadherin in PyMT or MCF-7 mammary tumor cells enhanced cell motility and caused a dramatic reduction in Akt3 expression and phosphorylation. Moreover, knockdown of Akt3 in PyMT tumor ...[more]

PMID: 22410780

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Project description:BackgroundOsteopontin is a secreted phosphoglycoprotein that is expressed by a number of normal cells as well as a variety of tumor cells. With respect to breast cancer, osteopontin has been implicated in regulating tumor cell proliferation and migration/metastasis and may serve as a prognostic indicator. However it remains unclear whether osteopontin has the same impact in all breast cancer subtypes and in particular, osteopontin's effects in claudin-low breast cancer are poorly understood.MethodscDNA microarrays and qRT-PCR were used to evaluate osteopontin expression in mammary tumors from MTB-IGFIR transgenic mice and cell lines derived from these tumors. siRNA was then used to determine the impact of osteopontin knockdown on proliferation, apoptosis and migration in vitro in two murine claudin-low cell lines as well as identify the receptor mediating osteopontin's physiologic effects.ResultsOsteopontin was expressed at high levels in mammary tumors derived from MTB-IGFIR transgenic mice compared to normal mammary tissue. Evaluation of cell lines derived from different mammary tumors revealed that mammary tumor cells with claudin-low characteristic expressed high levels of osteopontin whereas mammary tumor cells with mixed luminal and basal-like features expressed lower levels of osteopontin. Reduction of osteopontin levels using siRNA significantly reduced proliferation and migration while increasing apoptosis in the claudin-low cell lines. Osteopontin's effect appear to be mediated through a receptor containing ITGAV and not through CD44.ConclusionsOur data suggests that mammary tumors with a mixed luminal/basal-like phenotype express high levels of osteopontin however this osteopontin appears to be largely produced by non-tumor cells in the tumor microenvironment. In contrast tumor cells with claudin-low characteristics express high levels of osteopontin and a reduction of osteopontin in these cells impaired proliferation, survival and migration.

Dataset Information

N-cadherin regulates mammary tumor cell migration through Akt3 suppression.

Publications

N-cadherin regulates mammary tumor cell migration through Akt3 suppression.

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