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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 ?-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 ?-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 ?1/mTOR pathway. Thus, up-regulation of THBS1, TNC, FN, SPARC and ?-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 ?1/mTOR pathway, suggesting that therapies targeting integrin ?1/mTOR pathway may be a promising strategy to overcome chemotherapy resistance.

SUBMITTER: Wang T

PROVIDER: S-EPMC5342408 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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High expression of intratumoral stromal proteins is associated with chemotherapy resistance in breast cancer.

Wang Tingting T Srivastava Supriya S Hartman Mikael M Buhari Shaik Ahmad SA Chan Ching-Wan CW Iau Philip P Khin Lay Wai LW Wong Andrea A Tan Sing-Huang SH Goh Boon-Cher BC Lee Soo-Chin SC

Oncotarget 20160801 34

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 respect ...[more]

PMID: 27487140

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Project description:ObjectivesPrevious studies showed overexpression of ABCG2 in a variety of tumor tissues, which could potentially indicate the probability of chemotherapy resistance. This study aimed to reveal the role of ABCG2 in the development of chemotherapy resistance and the prognosis of osteosarcoma (OS).MethodsSixty-eight OS patients were included in this study. Tumor tissues were collected for each patient during surgery. DOX-resistant OS cell lines were induced by consecutive exposure of gradually increasing concentration of DOX to the parental cell lines. Lentivirus was used for the knockdown of ABCG2 in OS cells. Cells were treated with the gradient concentration of DOX, and the viability was assessed by CCK8 assay. Total RNA was isolated from the tumor tissues or tumor cells, and the expression of ABCG2 was analyzed by qPCR. The relationship between ABCG2 expression and clinicopathological characteristics of the patients was analyzed using Student's t test or the Chi-square test. The overall survival time was calculated by the Kaplan-Meier method and analyzed by the log-rank test. p < 0.05 was considered statistically significant.ResultsDOX-resistant OS cells were successfully established through continuous exposure to DOX. Forty-eight hours after DOX exposure, the IC 50 value of DOX-resistant HOS cells and DOX-resistant U2OS was 3.5 μM and 3.25 μM, respectively. By contrast, those of the untreated HOS and U2OS cells were 1.15 μM and 0.93 μM, respectively (p < 0.01). The mRNA expression level of ABCG2 was significantly increased in DOX-resistant cell lines. The CCK-8 assay showed that the DOX-resistant HOS cells and DOX-resistant U2OS cells transfected with ShABCG2 were more sensitive to the DOX treatment than those transfected with ShCtrl. Analysis of gene expression in OS tissues showed remarkably higher expression of ABCG2 as compared with adjacent normal tissues (p < 0.01). Patients with high expression level of ABCG2 had obviously decreased overall survival time than the patients with normal expression (p < 0.01).ConclusionsABCG2 expression level was significantly associated with the resistance to chemotherapy and the overall survival of OS patients. ABCG2 may be a promising therapeutic target for OS patients.

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High expression of intratumoral stromal proteins is associated with chemotherapy resistance in breast cancer.

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High expression of intratumoral stromal proteins is associated with chemotherapy resistance in breast cancer.

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