title: Hedgehog Acyltransferase as a target in estrogen receptor positive, HER2 amplified, and tamoxifen resistant breast cancer cells.
abstract: BACKGROUND
  Hedgehog acyltransferase (Hhat) catalyzes the transfer of the fatty acid palmitate onto Sonic Hedgehog (Shh), a modification that is essential for Shh signaling activity. The Shh signaling pathway has been implicated in the progression of breast cancer.
  
  
  METHODS
  To determine the functional significance of Hhat expression in breast cancer, we used a panel of breast cancer cell lines that included estrogen receptor (ER) positive, HER2 amplified, triple negative, and tamoxifen resistant cells. We monitored both anchorage dependent and independent proliferation of these cells following depletion of Hhat with lentiviral shRNA and inhibition of Hhat activity with RU-SKI 43, a small molecule inhibitor of Hhat.
  
  
  RESULTS
  Depletion of Hhat decreased anchorage-dependent and anchorage-independent proliferation of ER positive, but not triple negative, breast cancer cells. Treatment with RU-SKI 43 also reduced ER positive cell proliferation, whereas a structurally related, inactive compound had no effect. Overexpression of Hhat in ER positive cells not only rescued the growth defect in the presence of RU-SKI 43 but also resulted in increased cell proliferation in the absence of drug. Furthermore, depletion or inhibition of Hhat reduced proliferation of HER2 amplified as well as tamoxifen resistant cells. Inhibition of Smoothened had no effect on proliferation, indicating that canonical Shh signaling was not operative. Moreover, Hhat regulated the proliferation of both Shh responsive and non-responsive ER positive cells, suggesting a Shh independent function for Hhat.
  
  
  CONCLUSIONS
  These data suggest that Hhat plays a critical role in ER positive, HER2 amplified, and hormone resistant breast cancer proliferation and highlights the potential promise of Hhat inhibitors for therapeutic benefit in breast cancer.
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 143, New York, NY, 10065, USA. matevosa@mskcc.org.|Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. matevosa@mskcc.org.
authors.forename: Armine
authors.initials: A
authors.lastname: Matevossian
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 143, New York, NY, 10065, USA. reshm@mskcc.org.|Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. reshm@mskcc.org.
authors.forename: Marilyn D
authors.initials: MD
authors.lastname: Resh
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005784:Gene Amplification; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D000077341:Lapatinib; D021381:Protein Transport; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D000217:Acyltransferases; D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D053823:Hedgehog Proteins; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C506487:ESR1 protein, human; C509239:SHH protein, human; C105599:HHAT protein, human; C508053:ERBB2 protein, human