title: Identification of mTORC2 as a necessary component of HRG/ErbB2-dependent cellular transformation.
abstract: Overexpression of the receptor tyrosine kinase HER2/ErbB2 (ERBB2) has been linked to a poor prognosis for patients with breast cancer; thus, its activity is a central target for cancer therapy. Likewise, overexpression of heregulin (HRG/NRG1), a growth factor responsible for ErbB2 activation, has also been shown to be a driver of breast cancer progression. Although ErbB2 inhibitors offer a major advancement in the treatment of ErbB2-dependent breast cancers, patients are highly susceptible to developing clinical resistance to these drugs. Therefore, a detailed understanding of the molecular mechanism that underlies HRG/ErbB2-induced tumorigenesis is essential for the development of effective therapeutic strategies for this subset of patients with breast cancer. Here, it was demonstrated that HRG promoted anchorage-independent breast cancer cell growth more potently than EGF, and that the HRG-dependent activation of phosphoinositide 3-kinase and mTORC1 are necessary events for cell transformation. Functional evaluation of two distinct mTOR (MTOR) inhibitors, rapamycin and INK-128, on HRG-dependent signaling activities, uncovered a necessary role for mTORC2 in the regulation of the AKT/TSC2/mTORC1 axis by affecting the phosphorylation of AKT at the PDK1(PDPK1)-dependent site (T308) as well as at the mTORC2-dependent site (S473). The elimination of Rictor (RICTOR), a critical component of mTORC2, is detrimental to both the activation of mTORC1 and HRG-mediated cellular transformation. Similar results were obtained in multiple breast cancer model systems, highlighting an important role for mTORC2 in HRG/ErbB2-dependent breast cancer.
  
  
  CONCLUSIONS
  These findings suggest the potential benefits of targeting mTORC2 in HRG/ErbB2-induced breast cancer.
authors.affiliation: Authors' Affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York.
authors.forename: Miao-chong J
authors.initials: MC
authors.lastname: Lin
authors.affiliation: Authors' Affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Rojas
authors.affiliation: Authors' Affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York kw20@cornell.edu rac1@cornell.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
authors.affiliation: Authors' Affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York kw20@cornell.edu rac1@cornell.edu.
authors.forename: Kristin F
authors.initials: KF
authors.lastname: Wilson
mesh_terms: D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D020890:Neuregulin-1 / Q000378:metabolism*; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human