title: High expression of intratumoral stromal proteins is associated with chemotherapy resistance in breast cancer.
abstract: We studied the changes of intratumoral stromal proteins including THBS1, TNC, FN, SPARC and α-SMA, following neoadjuvant chemotherapy. The underlying mechanisms by which THBS1 and TNC regulated resistance to docetaxel were further studied using functional studies. 100 patients with newly diagnosed breast cancer were treated with alternating sequential doxorubicin and docetaxel. Immunohistochemistry (IHC) staining for stromal proteins was performed on pre- and post-treatment core biopsies respectively. THBS1 and TNC were further validated with IHC in an independent cohort of 31 patients. A high baseline combined expression score of the 5 stromal proteins predicted independently for poor progression-free (HRadjusted 2.22, 95% CI 1.06-4.64) and overall survival (HRadjusted 5.94, 95% CI 2.25-15.71). After 1-2 cycles of chemotherapy, increased expression of THBS1, TNC, FN, SPARC and α-SMA was seen in patients with subsequent pathological lymph node involvement at surgery. Increased expression of THBS1 and TNC compared to baseline was also seen in intrinsically resistant tumors, but not in sensitive ones. Both THBS1 and TNC-associated chemoresistance were confirmed in an independent validation cohort. Exogenous THBS1 and TNC protected MCF-7 cells against proliferation inhibition induced by docetaxel through activating integrin β1/mTOR pathway. Thus, up-regulation of THBS1, TNC, FN, SPARC and α-SMA following neoadjuvant chemotherapy was associated with chemotherapy resistance in breast cancer patients. Functional studies showed THBS1 and TNC to mediate chemoresistance through the integrin β1/mTOR pathway, suggesting that therapies targeting integrin β1/mTOR pathway may be a promising strategy to overcome chemotherapy resistance.
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore.
authors.forename: Supriya
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Department of Surgery, National University Cancer Institute, National University Health System, Singapore.|Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
authors.forename: Mikael
authors.initials: M
authors.lastname: Hartman
authors.affiliation: Department of Surgery, National University Cancer Institute, National University Health System, Singapore.
authors.forename: Shaik Ahmad
authors.initials: SA
authors.lastname: Buhari
authors.affiliation: Department of Surgery, National University Cancer Institute, National University Health System, Singapore.
authors.forename: Ching-Wan
authors.initials: CW
authors.lastname: Chan
authors.affiliation: Department of Surgery, National University Cancer Institute, National University Health System, Singapore.
authors.forename: Philip
authors.initials: P
authors.lastname: Iau
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
authors.forename: Lay Wai
authors.initials: LW
authors.lastname: Khin
authors.affiliation: Department of Haematology and Oncology, National University Cancer Institute, National University Health System, Singapore.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wong
authors.affiliation: Department of Haematology and Oncology, National University Cancer Institute, National University Health System, Singapore.
authors.forename: Sing-Huang
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore.|Department of Haematology and Oncology, National University Cancer Institute, National University Health System, Singapore.
authors.forename: Boon-Cher
authors.initials: BC
authors.lastname: Goh
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore.|Department of Haematology and Oncology, National University Cancer Institute, National University Health System, Singapore.
authors.forename: Soo-Chin
authors.initials: SC
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology; D008875:Middle Aged; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D019063:Tenascin / Q000032:analysis / Q000502:physiology*; D019700:Thrombospondin 1 / Q000032:analysis / Q000502:physiology*
chemical_list: D019012:Integrin beta1; D019063:Tenascin; D019700:Thrombospondin 1; C000611726:thrombospondin-1, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: breast cancer; cancer-associated stromal protein; chemotherapy resistance; integrin β; mTOR pathway