Abstract
BackgroundHuman sodium iodide symporter (hNIS) gene over-expression is under active consideration worldwide as an alternative target molecule for breast cancer (BC) diagnosis and targeted radio-iodine treatment. However, the field demands better stratified analysis of endogenous hNIS expression across major BC subtypes. Therefore, we have analyzed subtype-specific variation of hNIS overexpression in breast tumor tissue samples by immunohistochemistry (IHC) and also report the development of a homogeneous, quantitative analysis method of digital IHC images.MethodshNIS expression was analyzed from 108 BC tissue samples by IHC. Sub-cellular localization of hNIS protein was analyzed by dual immunofluorescence (IF) staining method using hNIS and HER2 antibodies. An ImageJ based two-step digital analysis method was developed and applied for the bias-free analysis of the images.ResultsStaining of the tumor samples show 70% cases are hNIS positive indicating high incidence of hNIS positive cases in BC. More importantly, a subtype specific analysis done for the first time shows that hNIS expression is overly dominated in estrogen receptor (ER) positive cases than the receptor negative cases. Further, 56% of the ER+ve, PgR+ve, HER2-ve and 36% of ER+ve, PgR+ve, HER2+ve cases show highest intensity staining equivalent to the thyroid tissue. A significant positive correlation is also observed between hNIS and estrogen receptor expression (p = 0.0033, CI = 95%) suggesting hNIS mediated targeted radio-iodine therapy procedures may benefit both ER+ve, PgR+ve, HER2–ve as well as HER2+ve cases. Further, in a few cases, hNIS and HER2 protein localization is demonstrated by overlapping membrane co-expression. ImageJ based image analysis method shows over 70% match with manual pathological scoring method.ConclusionThe study indicates a positive link between hNIS and ER expression in BC. The quantitative IHC image analysis method reported here will further help in patient stratification and potentially benefit global clinical assessment where hNIS mediated targeted 131I radio-ablative therapy is aimed.
Highlights
Since, the human sodium iodide symporter cDNA was cloned [1], attempts to examine its expression in various human non-thyroidal cell lines and correlate with its function as a membrane iodine transporter has been initiated
Results Human sodium iodide symporter (hNIS) Expression is Significantly Different in Major Subtypes of Breast Cancer
Subtype specific classification shows that more than 90% samples of estrogen receptor (ER)+ve, PgR +ve, HER2 -ve and 82% of ER+ve, PgR +ve, HER2+ve subtype are positive whereas only 70% HER2 enriched (ER-ve, PgR–ve, HER2+ve) and 56% of ER-ve, PgR–ve, HER2ve samples are positive for hNIS expression
Summary
The human sodium iodide symporter (hNIS) cDNA was cloned [1], attempts to examine its expression in various human non-thyroidal cell lines and correlate with its function as a membrane iodine transporter has been initiated. Tazebay et al demonstrated that above 80% of invasive and ductal carcinoma in situ (DCIS) samples express hNIS, whereas only 20% of tumor adjacent normal tissues express this protein [4]. It is evident from literature that hNIS can be effectively used as a functional reporter protein in non-thyroidal cells [13,14,15,16,17] All these evidences together suggest that 80% cases are positive compared to none in nonlactating normal breast and show promises in utilizing the overexpressing hNIS protein in breast cancer. We have analyzed subtype-specific variation of hNIS overexpression in breast tumor tissue samples by immunohistochemistry (IHC) and report the development of a homogeneous, quantitative analysis method of digital IHC images
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