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Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer.

ABSTRACT: Adjuvant chemotherapy for breast cancer after surgery has effectively lowered metastatic recurrence rates. However, a considerable proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes crucial for tumor response to specific chemotherapy drugs is a challenge but is necessary to improve outcomes. By using integrated genomics, we identified a small number of overexpressed and amplified genes from chromosome 8q22 that were associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. We confirmed the association in an analysis of multiple independent cohorts. SiRNA-mediated knockdown of either of two of these genes, the antiapoptotic gene YWHAZ and a lysosomal gene LAPTM4B, sensitized tumor cells to anthracyclines, and overexpression of either of the genes induced anthracycline resistance. Overexpression of LAPTM4B resulted in sequestration of the anthracycline doxorubicin, delaying its appearance in the nucleus. Overexpression of these two genes was associated with poor tumor response to anthracycline treatment in a neoadjuvant chemotherapy trial in women with primary breast cancer. Our results suggest that 8q22 amplification and overexpression of LAPTM4B and YWHAZ contribute to de novo chemoresistance to anthracyclines and are permissive for metastatic recurrence. Overexpression of these two genes may predict anthracycline resistance and influence selection of chemotherapy.

SUBMITTER: Li Y

PROVIDER: S-EPMC2826790 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer.

Li Yang Y Zou Lihua L Li Qiyuan Q Haibe-Kains Benjamin B Tian Ruiyang R Li Yan Y Desmedt Christine C Sotiriou Christos C Szallasi Zoltan Z Iglehart J Dirk JD Richardson Andrea L AL Wang Zhigang Charles ZC

Nature medicine 20100124 2

Adjuvant chemotherapy for breast cancer after surgery has effectively lowered metastatic recurrence rates. However, a considerable proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes crucial for tumor response to specific chemotherapy drugs is a challenge but is necessary to improve outcomes. By using integrated genomics, we identified a small number of overexpressed and amplified genes from chromosome 8q22 that were ass ...[more]

PMID: 20098429

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Project description:Abstract Introduction Response rates to chemotherapy remain highly variable in breast cancer patients. We set out to identify genes associated with chemotherapy resistance. We analyzed what is currently the largest single-institute set of gene expression profiles derived from breast cancers prior to a single neoadjuvant chemotherapy regimen (dose-dense doxorubicine and cyclophophamide). Methods We collected, gene expression-profiled and analyzed 178 HER2-negative breast tumor biopsies (‘NKI dataset’). We employed a recently developed approach for detecting imbalanced differential signal (DIDS) in order to identify markers of resistance to treatment. In contrast to traditional methods, DIDS is able to identify markers that show aberrant expression in only a small subgroup of the non-responder samples. Results We found a number of markers of resistance to anthracycline-based chemotherapy. We validated our findings by the analysis of three external datasets, which contained 456 HER2-negative samples in total. Since these external sets included patients who received differing treatment regimens we could only validate markers of general chemotherapy resistance. There was a highly significant overlap in the markers identified in the NKI dataset and the other three datasets. Five resistance markers, SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B, were identified in three of the four datasets (p-value overlap <1e-6). These five genes identified resistant tumors that could not have been identified by merely taking ER-status or proliferation into account. Conclusion The identification of these genes might lead to a better understanding of the mechanisms involved in (clinically) observed chemotherapy resistance and could possibly assist in the recognition of breast cancers in which chemotherapy does not contribute to response or survival. We collected, gene expression profiled and analyzed 178 HER2-negative breast tumor biopsies, obtained from patients scheduled to undergo neoadjuvant therapy.

Project description:Abstract Introduction Response rates to chemotherapy remain highly variable in breast cancer patients. We set out to identify genes associated with chemotherapy resistance. We analyzed what is currently the largest single-institute set of gene expression profiles derived from breast cancers prior to a single neoadjuvant chemotherapy regimen (dose-dense doxorubicine and cyclophophamide). Methods We collected, gene expression-profiled and analyzed 178 HER2-negative breast tumor biopsies (M-bM-^@M-^XNKI datasetM-bM-^@M-^Y). We employed a recently developed approach for detecting imbalanced differential signal (DIDS) in order to identify markers of resistance to treatment. In contrast to traditional methods, DIDS is able to identify markers that show aberrant expression in only a small subgroup of the non-responder samples. Results We found a number of markers of resistance to anthracycline-based chemotherapy. We validated our findings by the analysis of three external datasets, which contained 456 HER2-negative samples in total. Since these external sets included patients who received differing treatment regimens we could only validate markers of general chemotherapy resistance. There was a highly significant overlap in the markers identified in the NKI dataset and the other three datasets. Five resistance markers, SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B, were identified in three of the four datasets (p-value overlap <1e-6). These five genes identified resistant tumors that could not have been identified by merely taking ER-status or proliferation into account. Conclusion The identification of these genes might lead to a better understanding of the mechanisms involved in (clinically) observed chemotherapy resistance and could possibly assist in the recognition of breast cancers in which chemotherapy does not contribute to response or survival. We collected, gene expression profiled and analyzed 178 HER2-negative breast tumor biopsies, obtained from patients scheduled to undergo neoadjuvant therapy.

Project description:BackgroundPatients with isolated locoregional recurrences (ILRR) of breast cancer have a high risk of distant metastasis and death from breast cancer. We aimed to establish whether adjuvant chemotherapy improves the outcome of such patients.MethodsThe CALOR trial was a pragmatic, open-label, randomised trial that accrued patients with histologically proven and completely excised ILRR after unilateral breast cancer who had undergone a mastectomy or lumpectomy with clear surgical margins. Eligible patients were enrolled from hospitals worldwide and were centrally randomised (1:1) to chemotherapy (type selected by the investigator; multidrug for at least four courses recommended) or no chemotherapy, using permuted blocks, and stratified by previous chemotherapy, oestrogen-receptor and progesterone-receptor status, and location of ILRR. Patients with oestrogen-receptor-positive ILRR received adjuvant endocrine therapy, radiation therapy was mandated for patients with microscopically involved surgical margins, and anti-HER2 therapy was optional. The primary endpoint was disease-free survival. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00074152.FindingsFrom Aug 22, 2003, to Jan 31, 2010, 85 patients were randomly assigned to receive chemotherapy and 77 were assigned to no chemotherapy. At a median follow-up of 4·9 years (IQR 3·6-6 ·0), 24 (28%) patients had disease-free survival events in the chemotherapy group compared with 34 (44%) in the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56-79) with chemotherapy versus 57% (44-67) without chemotherapy (hazard ratio 0·59 [95% CI 0·35-0·99]; p=0·046). Adjuvant chemotherapy was significantly more effective for women with oestrogen-receptor-negative ILRR (pinteraction=0·046), but analyses of disease-free survival according to the oestrogen-receptor status of the primary tumour were not statistically significant (pinteraction=0·43). Of the 81 patients who received chemotherapy, 12 (15%) had serious adverse events. The most common adverse events were neutropenia, febrile neutropenia, and intestinal infection.InterpretationAdjuvant chemotherapy should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is oestrogen-receptor negative.FundingUS Department of Health and Human Services, Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australian and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK), Grupo Español de Investigación en Cáncer de Mama (GEICAM), and the Dutch Breast Cancer Trialists' Group (BOOG).

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Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer.

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Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer.

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