Proliferative genes dominate malignancy-risk gene signature in histologically-normal breast tissue

Abstract

PURPOSE-Historical data have indicated the potential for the histologically-normal breast to harbor pre-malignant changes at the molecular level. We postulated that a histologically-normal tissue with "tumor-like" gene expression pattern might harbor substantial risk for future cancer development. Genes associated with these high-risk tissues were considered to be "malignancy-risk genes".EXPERIMENTAL DESIGN-From a total of 90 breast cancer patients, we collected a set of 143 histologically-normal breast tissues derived from patients harboring breast cancer who underwent curative mastectomy, as well as a set of 42 invasive ductal carcinomas (IDC) of various histologic grades. All samples were assessed for global gene expression differences using microarray analysis. For the purpose of this study we defined normal breast tissue to include histologically normal and benign lesions.RESULTS-Here we report the discovery of a "malignancy-risk" gene signature that may portend risk of breast cancer development in benign, but molecularly-abnormal, breast tissue. Pathway analysis showed that the malignancy-risk signature had a dramatic enrichment for genes with proliferative function, but appears to be independent of ER, PR, and HER2 status. The signature was validated by RT-PCR, with a high correlation (Pearson correlation=0.95 with p<0.0001) with microarray data.CONCLUSION-These results suggest a predictive role for the malignancy-risk signature in normal breast tissue. Proliferative biology dominates the earliest stages of tumor development.While breast cancer therapy has seen substantial advances over the last few decades (1, 2 ), predicting breast cancer risk in the apparently normal breast is still problematic (3-9 ). AlthoughCorrespondence should be addressed to T.Y. (Timothy.Yeatman@moffitt.org).• Aejaz Nasir is a joining first author. NIH Public Access Author ManuscriptBreast Cancer Res Treat. Author manuscript; available in PMC 2011 January 1. Published in final edited form as:Breast Cancer Res Treat. 2010 January ; 119(2): 335-346. doi:10.1007/s10549-009-0344-y. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript a few pre-malignant histologic risk factors have been identified (atypical ductal hyperplasia (ADH), lobular carcinoma in situ, microcalcifications) (10, 11 ), few tools exist to distinguish the normal breast from the breast at risk for cancer (3-9 ). Furthermore, in patients who are treated for invasive breast cancer, the risk of local recurrence remains in spite of histologically negative margins. Wapnir et al (12) observed 10-year cumulative local recurrence rates ranging from 4.8% to 10.1% across five National Surgical Adjuvant Breast and Bowel Project (NSABP) trials involving 2,669 node-positive patients treated between 1984 and 1994, and 10-year local recurrence rates of 3.5% to 6.5% were observed in node-negative patients receiving systemic treatment in NSABP trials (13) during the same time period.Recent developments of gene signatures for breast cancer have been rep...

Gene expression in histologically normal epithelium from breast cancer patients and from cancer-free prophylactic mastectomy patients shares a similar profile

“…Investigations of gene expression in HN breast epithelium are limited (Finak et al, 2006;Grigoriadis et al, 2006;Tripathi et al, 2008;Chen et al, 2009). Our results contrast with one study that did not find a different gene expression between morphologically normal epithelium microdissected from RM and HN samples (Finak et al, 2006).…”

“…Another study (Chen et al, 2009) found a proliferative gene expression signature in morphologically benign tissue (not necessarily HN) of patients with invasive carcinoma, but no controls were reported. Third, evaluation of the RM -HN gene list leads to several speculations.…”

“…Much less is known about the gene expression in premalignant breast tissue, and studies that focused on HN epithelium (NlEpi) are particularly limited (Finak et al, 2006;Grigoriadis et al, 2006;Tripathi et al, 2008;Chen et al, 2009). This is partly because of the difficulty in obtaining homogeneous epithelial cell populations from fresh tissue.…”

“…the Gail model (Gail et al, 1989(Gail et al, , 2007) to improve their accuracy. Some evidence already exists suggesting that alterations could have clinical significance (Yang et al, 2005;Chen et al, 2009). In our pilot study, using a different statistical approach and study design, we identified the differences in gene expression between microdissected NlEpi of controls (women undergoing reduction mammoplasty (RM)) and those of cases (women with oestrogen receptor (ER) þ breast cancers) (Tripathi et al, 2008).…”

Data driven derivation of cutoffs from a pool of 3,030 Affymetrix arrays to stratify distinct clinical types of breast cancer

“…We included 238 of our own samples (datasets Frankfurt, Frankfurt-2, and Frankfurt-3) which have been described previously (Ahr et al 2002 [9], [10], Rody et al 2008 [11], Ruckhäberle et al 2008 [12], and Rody et al 2007 [13], respectively) as well as 2792 samples from 22 different publicly available datasets (Table 1): Rotterdam [14][15][16], Mainz [17], Trans-BIG [18], Oxford-Untreated [19], London [20], London-2 [21], Oxford-Tamoxifen, Veridex-Tam [22], Stockholm [23], Uppsala [24,25], San Francisco [26], New York [27], MDA133 [28], EORTC [29], Edinburgh [30], ExpO [31], Signapore [32], Genentech [33], Boston [34], Berlin [35], Paris [36], and Tampa [37]. For comparability, only the ProbeSets from the Affymetrix HG-U133A microarray were used from seven datasets where HG-U133?…”