Myocardin-related transcription factor A is up-regulated by 17β-estradiol and promotes migration of MCF-7 breast cancer cells via transactivation of <italic>MYL9</italic> and <italic>CYR61</italic>

Abstract

Many lines of evidence have suggested that estrogen plays important roles not only in the initiation and proliferation of breast cancer, but also in cancer metastasis. However, the mechanistic basis of the latter events is poorly understood. In addition, recent studies have suggested that myocardin-related transcription factor A (MRTF-A) might be related to cancer metastasis. However, as reports are contradictory, certain of its roles still remain confusing. In the present study, we showed that excessive 17b-estradiol could promote the migration of MCF-7 breast cancer cells and up-regulate the expression of MRTF-A, myosin regulatory light chain 9 (MYL9), and cysteine-rich angiogenic inducer 61 (CYR61). Overexpression of MRTF-A significantly promoted the migration of MCF-7 cells through its transactivation effects on MYL9 and CYR61 genes, while RNA interference-mediated knockdown of MRTF-A strongly inhibited transcription and expression of the target genes and reduced the migration ability of MCF-7 cells. These results provided novel evidence supporting the metastasispromoting functions of MRTF-A, and implied that MRTF-A might be a switch for the estrogen pathway to change its proliferation-promoting roles into migration-stimulating roles in breast cancer.

SRF'ing and SAP'ing – the role of MRTF proteins in cell migration

“…cytoskeleton, reduced contractility and impaired motility of MRTFA-deficient neutrophils were correlated with the reduced expression of several actin regulators and actin-cytoskeleton-related proteins, including CDC42BPA and B, cortactin, FNBP1L (a positive regulator of actin polymerization depending on Cdc42 and/or N-WASP) and Myl9 (a component of myosin II) (Record et al, 2015). At least in MCF7 breast cancer cells, Myl9 upregulation was partly responsible for a MRTFA-induced hypermotile phenotype (Luo et al, 2014;Zhang et al, 2013). The ability of MRTFA to regulate the expression of factors that affect actomyosin contractility, such as Myl9, explains why it has a pivotal role in contractility-inducing cellular transitions, including epithelial-to-myofibroblast transformation (EmyT) and fibroblastto-myofibroblast transformation (FMyT) (Lighthouse and Small, 2016;O'Connor and Gomez, 2013;Small, 2012;Trembley et al, 2015;Velasquez et al, 2013).…”

“…Likewise, pharmacological inhibition of MRTF-SRF signaling through the MRTF inhibitor CCG-1423 (Hayashi et al 2014) or its derivative CCG-203971 inhibited migration and invasion of melanoma (Watanabe et al, 2015) and prostate (Evelyn et al, 2010(Evelyn et al, , 2016 cancer cells in vitro, and experimental lung metastasis of melanoma cells in vivo (Haak et al, 2017). By contrast, overexpression of MRTFA stimulated motility of the non-invasive MCF-7 breast cancers (Luo et al, 2014;Zhang et al, 2013). Several other studies correlated the alteration in either expression or localization of MRTFs to phenotypes of cell motility in response to different molecular and pharmacological perturbations.…”

Verteporfin Inhibits Cell Proliferation and Induces Apoptosis in Different Subtypes of Breast Cancer Cell Lines Without Light Activation

“…CCN intervenes in embryonic development, angiogenesis, tumor heterogeneity and progression through various signaling pathways, including the Hippo pathway [39][40]. Genetic studies have indicated that stable levels of CYR61 in MCF-7 cells is able to significantly counteract paclitaxel-induced apoptosis and increase chemotherapy resistance to doxorubicin [41]. In our study, we found that the treatment with VP of Luminal A MCF-7 cells downregulated the expression of CYR61, thereby suppressing the proliferation of MCF-7 cells and providing a new treatment strategy for Luminal A endocrine patients.…”

Extracellular matrix in obesity – cancer interactions

“…With some exceptions, CCN1, CCN2, and CCN4 have been usually associated with promotion of cell proliferation and tumor growth, whereas CCN3, CCN5, and CCN6 have opposite effects [137]. Zhang et al provided evidence that 17β-estradiol exposure induced the synthesis of CCN1 in MCF-7 breast cancer cells [138]. Of note, a major source of estrogen in postmenopausal women is by aromatization in adipose tissue; therefore, obesity is a major risk factor for breast cancer.…”

“…CCN1 can also be upregulated by EGF in MCF-7 cells [139]. Estrogenic upregulation of CCN1 can provide Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/25/15 10:38 AM new insight as a possible underlying mechanism in breast cancer pathology [138,139]. In MCF-7 breast cancer cell line, Chien et al demonstrated that forced overexpression of CTGF lead to stimulation of angiogenesis and promoted migration [140].…”