Activation of the MKL1/actin signaling pathway induces hormonal escape in estrogen-responsive breast cancer cell lines

Abstract

Estrogen receptor alpha (ERα) is generally considered to be a good prognostic marker because almost 70% of ERα-positive tumors respond to anti-hormone therapies. Unfortunately, during cancer progression, mammary tumors can escape from estrogen control, resulting in resistance to treatment. In this study, we demonstrate that activation of the actin/megakaryoblastic leukemia 1 (MKL1) signaling pathway promotes the hormonal escape of estrogen-sensitive breast cancer cell lines. The actin/MKL1 signaling pathway is silenced in differentiated ERα-positive breast cancer MCF-7 and T47D cell lines and active in ERα-negative HMT-3522 T4-2 and MDA-MB-231 breast cancer cells, which have undergone epithelial-mesenchymal transition. We showed that MKL1 activation in MCF-7 cells, either by modulating actin dynamics or using MKL1 mutants, down-regulates ERα expression and abolishes E2-dependent cell growth. Interestingly, the constitutively active form of MKL1 represses PR and HER2 expression in these cells and increases the expression of HB-EGF, TGFβ, and amphiregulin growth factors in an E2-independent manner. The resulting expression profile (ER-, PR-, HER2-) typically corresponds to the triple-negative breast cancer expression profile.

Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

“…Interestingly, there is accumulating data that MKL1 may have both tumor inhibiting and tumor promoting roles depending on the cellular context. Recently, it was shown that the MKL1 signaling pathway was activated in ER-cell lines and silenced in ER+ cell lines 29 . Additionally, the MKL1 breast cancer SNP has been shown to be associated with triple negative breast cancer 30 .…”

Down-regulation of hTERT and Cyclin D1 transcription via PI3K/Akt and TGF-β pathways in MCF-7 Cancer cells with PX-866 and Raloxifene

“…Abnormal transcription levels of LIF , HB EGF and ER α are indicated with activation of the actin/megakaryoblastic leulemia 1 (MKL1) pathway, and the resulting phenotype with decreased ERα and increased HB EGF resembles triple-negative breast cancer, with proliferation driven by growth factors rather than hormones [42, 72]. When highly expressed, HB EGF binds to epidermal growth factor receptors to promote growth and more aggressive and invasive forms of cancer [73, 42].…”

“…When highly expressed, HB EGF binds to epidermal growth factor receptors to promote growth and more aggressive and invasive forms of cancer [73, 42]. With almost every expression profile gene we examined, the expression level after treatment with PX-866 and/or raloxifene was in direct contrast with that in the pathological expression profile.…”

“…One reported signature of TGF-β pathway misdirection includes Interleukin 11 (IL-11) , Cyclin D1 and Axin2 as genes with transcription levels most divergent from normal [41]. Another includes Leukemia inhibitory factor (LIF), HB EGF and ER α with most divergent transcription levels [42]. …”

MKL1 and STAT3 activate the activity of the luciferase reporter plasmid containing the CAAP1 gene promoter

“…Signal transduction and activator of transcription 3 (STAT3) is widely expressed in a variety of cells and participates in the regulation of physiological functions and pathological processes such as cell growth process, malignant transformation process, and cell apoptosis [11,12]. Over-activation of STAT3 promotes proliferation, apoptosis and migration of breast cancer cells, and can also lead to malignant transformation of normal breast cells [13][14][15].…”