Hypoxic regulation and prognostic value of LAMP3 expression in breast cancer

BACKGROUND: LAMP3 is a newly described hypoxia regulated gene of potential interest in hypoxia‐induced therapy resistance and metastasis. The prognostic value of LAMP3 in breast cancer was investigated. METHODS: Expression levels of LAMP3 in breast cancer cell lines and patient tissues were determin...

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Published in:Cancer 2011-08, Vol.117 (16), p.3670-3681
Main Authors: Nagelkerke, Anika, Mujcic, Hilda, Bussink, Johan, Wouters, Bradly G., van Laarhoven, Hanneke W. M., Sweep, Fred C. G. J., Span, Paul N.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
breast neoplasms
Breast Neoplasms - genetics
Breast Neoplasms - mortality
Cell Hypoxia - genetics
Cell Line, Tumor
DC‐LAMP
Female
Gene Expression Regulation, Neoplastic
Gynecology. Andrology. Obstetrics
Humans
hypoxia
Lymphatic Metastasis
Lysosomal Membrane Proteins - genetics
Mammary gland diseases
Medical sciences
metastasis
Mice
Mice, Nude
Neoplasm Proteins - genetics
Neoplasm Recurrence, Local
Neoplasm Transplantation
Oxygen - metabolism
Prognosis
TSC403
Tumors
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Summary:BACKGROUND: LAMP3 is a newly described hypoxia regulated gene of potential interest in hypoxia‐induced therapy resistance and metastasis. The prognostic value of LAMP3 in breast cancer was investigated. METHODS: Expression levels of LAMP3 in breast cancer cell lines and patient tissues were determined by real‐time polymerase chain reaction and in a tissue microarray by immunohistochemistry. Immunofluorescent staining was used to evaluate the distribution of LAMP3 in tumor xenografts relative to pimonidazole. Kaplan‐Meier analysis as well as multivariate Cox regression survival analyses were performed. RESULTS: LAMP3 was variably expressed in breast cancer cell lines and induced in an oxygen concentration‐dependent manner. LAMP3 protein expression colocalized with hypoxic areas in breast cancer xenografts. LAMP3 mRNA was higher in breast tumors from patients with node‐positive (P = .019) and/or steroid hormone receptor‐negative tumors (P < .001). Breast cancer patients with high LAMP3 mRNA levels had more locoregional recurrences (P = .032 log‐rank). This was limited to patients treated with lumpectomy and radiotherapy as primary treatment (n = 53, P = .009). No association with metastasis‐free survival was found. In multivariate Cox regression analysis, LAMP3 remained as a statistically independent prognostic factor for locoregional recurrence (hazard ratio, 2.76; 95% confidence interval, 1.01‐7.5; P = .048) after correction for menopausal status, histologic grade, tumor size, nodal status, therapy, and steroid hormone receptor status. LAMP3 protein in breast cancer tissue proved also to be of prognostic relevance. CONCLUSIONS: Evidence was provided for an association of LAMP3 with tumor cell hypoxia in breast cancer xenografts. In the current breast cancer cohorts, LAMP3 had independent prognostic value. Cancer 2011;117:3670–3681. © 2011 American Cancer Society. LAMP3 was found to be associated with hypoxia in breast cancer cell lines, xenografts, and tissues. In a cohort of breast cancer patients, LAMP3 mRNA and protein had independent prognostic value.
ISSN:0008-543X
1097-0142
DOI:10.1002/cncr.25938