Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomesReport as inadecuate




Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes - Download this document for free, or read online. Document in PDF available to download.

Breast Cancer Research

, 14:R130

First Online: 04 October 2012Received: 17 April 2012Revised: 07 August 2012Accepted: 04 October 2012

Abstract

IntroductionSignal transducer and activator of transcripton-5a Stat5a and its close homologue, Stat5b, mediate key physiological effects of prolactin and growth hormone in mammary glands. In breast cancer, loss of nuclear localized and tyrosine phosphorylated Stat5a-b is associated with poor prognosis and increased risk of antiestrogen therapy failure. Here we quantify for the first time levels of Stat5a and Stat5b over breast cancer progression, and explore their potential association with clinical outcome.

MethodsStat5a and Stat5b protein levels were quantified in situ in breast-cancer progression material. Stat5a and Stat5b transcript levels in breast cancer were correlated with clinical outcome in 936 patients. Stat5a protein was further quantified in four archival cohorts totaling 686 patients with clinical outcome data by using multivariate models.

ResultsProtein levels of Stat5a but not Stat5b were reduced in primary breast cancer and lymph node metastases compared with normal epithelia. Low tumor levels of Stat5a but not Stat5b mRNA were associated with poor prognosis. Experimentally, only limited overlap between Stat5a- and Stat5b-modulated genes was found. In two cohorts of therapy-naïve, node-negative breast cancer patients, low nuclear Stat5a protein levels were an independent marker of poor prognosis. Multivariate analysis of two cohorts treated with antiestrogen monotherapy revealed that low nuclear Stat5a levels were associated with a more than fourfold risk of unfavorable outcome.

ConclusionsLoss of Stat5a represents a new independent marker of poor prognosis in node-negative breast cancer and may be a predictor of response to antiestrogen therapy if validated in randomized clinical trials.

AbbreviationsAQUAAutomated quantitative analysis

CIconfidence interval

CSSbreast cancer-specific survival

DAB-IHCDAB-chromogen immunohistochemistry

DCISductal carcinoma in situ

ERestrogen receptor

FDRfalse discovery rate

HRhazard ratio

IDCinvasive ductal carcinoma

IQRinterquartile range

LNlymph node

LN Metlymph node metastasis

Nuc-pYStat5a-bnuclear localized and tyrosine phosphorylated Stat5a-b

Nuc-Stat5anuclear localized Stat5a

Nuc-Stat5bnuclear localized Stat5b

PRprogesterone receptor

SDstandard deviation

Stat5asignal transducer and activator of transcription-5a

Stat5bsignal transducer and activator of transcription-5b

TTRtime to breast cancer recurrence.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr3328 contains supplementary material, which is available to authorized users.

and Hallgeir Rui contributed equally to this work.

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Author: Amy R Peck - Agnieszka K Witkiewicz - Chengbao Liu - Alexander C Klimowicz - Ginger A Stringer - Edward Pequignot - Bori

Source: https://link.springer.com/article/10.1186/bcr3328







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