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CCN5/WISP-2 restores ER-? in normal and neoplastic breast cells and sensitizes triple negative breast cancer cells to tamoxifen.

ABSTRACT: CCN5/WISP-2 is an anti-invasive molecule and prevents breast cancer (BC) progression. However, it is not well understood how CCN5 prevents invasive phenotypes of BC cells. CCN5 protein expression is detected in estrogen receptor-? (ER-?) -positive normal breast epithelial cells as well as BC cells, which are weakly invasive and rarely metastasize depending on the functional status of ER-?. A unique molecular relation between CCN5 and ER-? has been established as the components of the same signaling pathway that coordinate some essential signals associated with the proliferation as well as delaying the disease progression from a non-invasive to invasive phenotypes. Given the importance of this connection, we determined the role of CCN5 in regulation of ER-? in different cellular settings and their functional relationship. In a genetically engineered mouse model, induced expression of CCN5 in the mammary ductal epithelial cells by doxycycline promotes ER-? expression. Similarly, CCN5 regulates ER-? expression and activity in normal and neoplastic breast cells, as documented in various in vitro settings such as mouse mammary gland culture, human mammary epithelial cell and different BC cell cultures in the presence or absence of human recombinant CCN5 (hrCCN5) protein. Mechanistically, at least in the BC cells, CCN5 is sufficient to induce ER-? expression at the transcription level via interacting with integrins-?6?1 and suppressing Akt followed by activation of FOXO3a. Moreover, in vitro and in vivo functional assays indicate that CCN5 treatment promotes response to tamoxifen in triple-negative BC (TNBC) cells possibly via restoring ER-?. Collectively, these studies implicates that the combination treatments of CCN5 (via activation of CCN5 or hrCCN5 treatment) and tamoxifen as potential therapies for TNBC.

SUBMITTER: Sarkar S

PROVIDER: S-EPMC5569333 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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CCN5/WISP-2 restores ER-∝ in normal and neoplastic breast cells and sensitizes triple negative breast cancer cells to tamoxifen.

Sarkar S S Ghosh A A Banerjee S S Maity G G Das A A Larson M A MA Gupta V V Haque I I Tawfik O O Banerjee S K SK

Oncogenesis 20170522 5

CCN5/WISP-2 is an anti-invasive molecule and prevents breast cancer (BC) progression. However, it is not well understood how CCN5 prevents invasive phenotypes of BC cells. CCN5 protein expression is detected in estrogen receptor-α (ER-α) -positive normal breast epithelial cells as well as BC cells, which are weakly invasive and rarely metastasize depending on the functional status of ER-α. A unique molecular relation between CCN5 and ER-α has been established as the components of the same signal ...[more]

PMID: 28530705

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Project description:Unlike breast cancer that is positive for estrogen receptor-? (ER?), there are no targeted therapies for triple-negative breast cancer (TNBC). ER? is silenced in TNBC through epigenetic changes including DNA methylation and histone acetylation. Restoring ER? expression in TNBC may sensitize patients to endocrine therapy. Expression of c-Src and ER? are inversely correlated in breast cancer suggesting that c-Src inhibition may lead to reexpression of ER? in TNBC. KX-01 is a peptide substrate-targeted Src/pretubulin inhibitor in clinical trials for solid tumors. KX-01 (1 mg/kg body weight-twice daily) inhibited growth of tamoxifen-resistant MDA-MB-231 and MDA-MB-157 TNBC xenografts in nude mice that was correlated with Src kinase inhibition. KX-01 also increased ER? mRNA and protein, as well as increased the ER? targets progesterone receptor (PR), pS2 (TFF1), cyclin D1 (CCND1), and c-myc (MYC) in MDA-MB-231 and MDA-MB-468, but not MDA-MB-157 xenografts. MDA-MB-231 and MDA-MB-468 tumors exhibited reduction in mesenchymal markers (vimentin, ?-catenin) and increase in epithelial marker (E-cadherin) suggesting mesenchymal-to-epithelial transition (MET). KX-01 sensitized MDA-MB-231 and MDA-MB-468 tumors to tamoxifen growth inhibition and tamoxifen repression of the ER? targets pS2, cyclin D1, and c-myc. Chromatin immunoprecipitation (ChIP) of the ER? promoter in KX-01-treated tumors demonstrated enrichment of active transcription marks (acetyl-H3, acetyl-H3Lys9), dissociation of HDAC1, and recruitment of RNA polymerase II. Methylation-specific PCR and bisulfite sequencing demonstrated no alteration in ER? promoter methylation by KX-01. These data demonstrate that in addition to Src kinase inhibition, peptidomimetic KX-01 restores ER? expression in TNBC through changes in histone acetylation that sensitize tumors to tamoxifen.Implications: Src kinase/pretubulin inhibitor KX-01 restores functional ER? expression in ER?- breast tumors, a novel treatment strategy to treat triple-negative breast cancer. Mol Cancer Res; 15(11); 1491-502. ©2017 AACR.

Dataset Information

CCN5/WISP-2 restores ER-? in normal and neoplastic breast cells and sensitizes triple negative breast cancer cells to tamoxifen.

Publications

CCN5/WISP-2 restores ER-∝ in normal and neoplastic breast cells and sensitizes triple negative breast cancer cells to tamoxifen.

Similar Datasets

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