title: Attenuated transforming growth factor beta signaling promotes metastasis in a model of HER2 mammary carcinogenesis.
abstract: BACKGROUND
  Transforming growth factor beta (TGFβ) plays a major role in the regulation of tumor initiation, progression, and metastasis. It is depended on the type II TGFβ receptor (TβRII) for signaling. Previously, we have shown that deletion of TβRII in mammary epithelial of MMTV-PyMT mice results in shortened tumor latency and increased lung metastases. However, active TGFβ signaling increased the number of circulating tumor cells and metastases in MMTV-Neu mice. In the current study, we describe a newly discovered connection between attenuated TGFβ signaling and human epidermal growth factor receptor 2 (HER2) signaling in mammary tumor progression.
  
  
  METHODS
  All studies were performed on MMTV-Neu mice with and without dominant-negative TβRII (DNIIR) in mammary epithelium. Mammary tumors were analyzed by flow cytometry, immunohistochemistry, and immunofluorescence staining. The levels of secreted proteins were measured by enzyme-linked immunosorbent assay. Whole-lung mount staining was used to quantitate lung metastasis. The Cancer Genome Atlas (TCGA) datasets were used to determine the relevance of our findings to human breast cancer.
  
  
  RESULTS
  Attenuated TGFβ signaling led to a delay tumor onset, but increased the number of metastases in MMTVNeu/DNIIR mice. The DNIIR tumors were characterized by increased vasculogenesis, vessel leakage, and increased expression of vascular endothelial growth factor (VEGF). During DNIIR tumor progression, both the levels of CXCL1/5 and the number of CD11b+Gr1+ cells and T cells decreased. Analysis of TCGA datasets demonstrated a significant negative correlation between TGFBR2 and VEGF genes expression. Higher VEGFA expression correlated with shorter distant metastasis-free survival only in HER2+ patients with no differences in HER2-, estrogen receptor +/- or progesterone receptor +/- breast cancer patients.
  
  
  CONCLUSIONS
  Our studies provide insights into a novel mechanism by which epithelial TGFβ signaling modulates the tumor microenvironment, and by which it is involved in lung metastasis in HER2+ breast cancer patients. The effects of pharmacological targeting of the TGFβ pathway in vivo during tumor progression remain controversial. The targeting of TGFβ signaling should be a viable option, but because VEGF has a protumorigenic effect on HER2+ tumors, the targeting of this protein could be considered when it is associated with attenuated TGFβ signaling.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Novitskiy
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Forrester
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pickup
authors.forename: Agnieszka E
authors.initials: AE
authors.lastname: Gorska
authors.forename: Anna
authors.initials: A
authors.lastname: Chytil
authors.forename: Mary
authors.initials: M
authors.lastname: Aakre
authors.forename: Dina
authors.initials: D
authors.lastname: Polosukhina
authors.forename: Philip
authors.initials: P
authors.lastname: Owens
authors.forename: Dilyara R
authors.initials: DR
authors.lastname: Yusupova
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhao
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018925:Chemokines; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C524056:Erbb2 protein, mouse