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

MOLECULAR AND CELLULAR ENDOCRINOLOGY

卷:390

Article

Kerdivel, Gwenneg¹  Boudot, Antoine¹  Habauzit, Denis¹  Percevault, Frederic¹  Demay, Florence¹  Pakdel, Farzad¹  Flouriot, Gilles¹ 

[1] Univ Rennes 1, IRSET, INSERM, Team TREC,Biosit,U1085, F-35042 Rennes, France

关键词: MKL1;    Hormone resistance;    Breast cancer;    Cell growth;    Estrogen receptor;    Tamoxifen;   

DOI  :  10.1016/j.mce.2014.03.009

来源: Elsevier

【 摘 要 】

Estrogen receptor alpha (ER alpha) is generally considered to be a good prognostic marker because almost 70% of ER alpha.-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 ER alpha-positive breast cancer MCF-7 and T47D cell lines and active in ER alpha-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 ER alpha 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, TGF beta, 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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

【 授权许可】

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