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MED12 controls the response to multiple cancer drugs through regulation of TGF-? receptor signaling.

ABSTRACT: Inhibitors of the ALK and EGF receptor tyrosine kinases provoke dramatic but short-lived responses in lung cancers harboring EML4-ALK translocations or activating mutations of EGFR, respectively. We used a large-scale RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex that is mutated in cancers, as a determinant of response to ALK and EGFR inhibitors. MED12 is in part cytoplasmic where it negatively regulates TGF-?R2 through physical interaction. MED12 suppression therefore results in activation of TGF-?R signaling, which is both necessary and sufficient for drug resistance. TGF-? signaling causes MEK/ERK activation, and consequently MED12 suppression also confers resistance to MEK and BRAF inhibitors in other cancers. MED12 loss induces an EMT-like phenotype, which is associated with chemotherapy resistance in colon cancer patients and to gefitinib in lung cancer. Inhibition of TGF-?R signaling restores drug responsiveness in MED12(KD) cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12.

SUBMITTER: Huang S

PROVIDER: S-EPMC3672971 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling.

Huang Sidong S Hölzel Michael M Knijnenburg Theo T Schlicker Andreas A Roepman Paul P McDermott Ultan U Garnett Mathew M Grernrum Wipawadee W Sun Chong C Prahallad Anirudh A Groenendijk Floris H FH Mittempergher Lorenza L Nijkamp Wouter W Neefjes Jacques J Salazar Ramon R Ten Dijke Peter P Uramoto Hidetaka H Tanaka Fumihiro F Beijersbergen Roderick L RL Wessels Lodewyk F A LF Bernards René R

Cell 20121101 5

Inhibitors of the ALK and EGF receptor tyrosine kinases provoke dramatic but short-lived responses in lung cancers harboring EML4-ALK translocations or activating mutations of EGFR, respectively. We used a large-scale RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex that is mutated in cancers, as a determinant of response to ALK and EGFR inhibitors. MED12 is in part cytoplasmic where it negatively regulates TGF-βR2 through physical interaction. MED12 suppression ...[more]

PMID: 23178117

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Project description:Among all tissues and organs, the mammary gland is unique because most of its development occurs in adulthood. Notch signaling has a major role in mammary gland development and has been implicated in breast cancer. The vacuolar-ATPase (V-ATPase) is a proton pump responsible for the regulation and control of pH in intracellular vesicles and the extracellular milieu. We have previously reported that a2V-ATPase (a2V), an isoform of 'a' subunit of V-ATPase, regulates processing of Notch receptor and alters Notch signaling in breast cancer. To study the role of a2V in mammary gland development, we generated an a2V-KO model (conditional mammary knockout a2V mouse strain). During normal mammary gland development, the basal level expression of a2V increased from puberty, virginity, and pregnancy through the lactation stage and then decreased during involution. Litters of a2V-KO mice weighed significantly less when compared with litters from wild-type mice and showed reduced expression of the lactation marker β-casein. Whole-mount analysis of mammary glands demonstrated impaired ductal elongation and bifurcation in a2V-KO mice. Consequently, we found disintegrated mammary epithelium as seen by basal and luminal epithelial staining, although the rate of proliferation remained unchanged. Delayed mammary morphogenesis in a2V-KO mice was associated with aberrant activation of Notch and TGF-β (transforming growth factor-β) pathways. Notably, Hey1 (hairy/enhancer-of-split related with YRPW motif) and Smad2, the key downstream mediators of Notch and TGF-β pathways, respectively, were upregulated in a2V-KO mice and also in human mammary epithelial cells treated with a2V siRNA. Taken together, our results show that a2V deficiency disrupts the endolysosomal route in Notch and TGF signaling, thereby impairing mammary gland development. Our findings have broader implications in developmental and oncogenic cellular environments where V-ATPase, Notch and TGF-β are crucial for cell survival.

Dataset Information

MED12 controls the response to multiple cancer drugs through regulation of TGF-? receptor signaling.

Publications

MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling.

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