Activation of the MKL1/actin signaling pathway induces hormonal escape in estrogen-responsive breast cancer cell lines.
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.
University of Rennes 1, Institut de Recherche en Santé Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Rennes, France.
Gwenneg
G
Kerdivel
University of Rennes 1, Institut de Recherche en Santé Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Rennes, France.
Antoine
A
Boudot
University of Rennes 1, Institut de Recherche en Santé Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Rennes, France.
Denis
D
Habauzit
University of Rennes 1, Institut de Recherche en Santé Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Rennes, France.
Frederic
F
Percevault
University of Rennes 1, Institut de Recherche en Santé Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Rennes, France.
Florence
F
Demay
University of Rennes 1, Institut de Recherche en Santé Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Rennes, France.
Farzad
F
Pakdel
University of Rennes 1, Institut de Recherche en Santé Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Rennes, France. Electronic address: gilles.flouriot@univ-rennes1.fr.
Gilles
G
Flouriot
D000199:Actins / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D015534:Trans-Activators; D014158:Transcription, Genetic
D000199:Actins; D018931:Antineoplastic Agents, Hormonal; D004268:DNA-Binding Proteins; D004958:Estradiol; D047628:Estrogen Receptor alpha; D015514:Oncogene Proteins, Fusion; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D013629:Tamoxifen; D015534:Trans-Activators; C506487:ESR1 protein, human; C431575:MRTFA protein, human; C508053:ERBB2 protein, human
Breast cancer; Cell growth; Estrogen receptor; Hormone resistance; MKL1; Tamoxifen