Holowatyj, Andreana N.

Abstract Benign breast disease, a known risk factor for subsequent breast cancer, includes a histological spectrum of lesions that can be subdivided based on the overall impression into non-proliferative lesions, proliferative lesions without atypia, and atypical hyperplasia. Yet little is known about the molecular characteristics of benign breast tissue from African American women, who suffer from disproportionately high breast cancer mortality rates. 72 breast samples from African American women were obtained. RNA was extracted from archival formalin-fixed, paraffin-embedded (FFPE) blocks. Gene expression profiling was performed on these samples using the Affymetrix HTA2.0 exon array chip. A fit linear model using generalized least squares identified probe sets with differential expression in benign-in situ and benign-invasive breast cancer paired lesions. 36 benign and 36 breast cancer paired lesions were included in the study. In the benign-in situ set (n=20), 978 probe sets were differentially expressed (threshold: fold-change, 1.50; p < 0.05). Probe sets mapped to 125 annotated genes, of which 69 (55.2%) were involved in cancer. The benign-invasive set (n=52) identified 351 differentially expressed probe sets that mapped to 84 annotated genes, of which 61 (72.6%) had known cancer significance. Genes involved in cellular growth and proliferation were significantly over-expressed in both benign-in situ and benign-invasive lesions (p-values < 0.0104). In the population of 36 paired samples, differentially expressed genes were found to regulate the estrogen receptor (ESR1) through distinct network associations. Many genes are differentially expressed by benign and breast cancer lesions, and in situ/invasive histology contribute to the distinct molecular characteristics and pathways of breast malignancy. Our findings highlight the first study to assess expression profiling of paired benign and breast cancer lesions among African American women. Citation Format: Andreana Natalie Holowatyj, Julie J. Ruterbusch, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay, Christine Mehner, Melody Stallings Mann, Gregory Dyson, Derek Radisky, Michele L. Cote. Expression profiling of paired benign and breast cancer lesions in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4253. doi:10.1158/1538-7445.AM2017-4253

Abstract An estimated 1.6 million breast biopsies are performed annually in the United States, and the vast majority are benign. Benign breast disease is an established breast cancer risk factor for both Caucasian and African American women. Yet little is still known about benign breast tissue from African American women, who suffer from disproportionately high-grade tumors and poorer breast cancer survival. To better characterize the risk of breast cancer among African American women with benign breast disease, we assessed benign breast disease pathology of African American women in our metropolitan Detroit cohort (n = 3,737). We classified benign breast lesions for pathological characteristics and used logistic regression to estimate subsequent breast cancer risk with histological characteristics. We observed that women whose biopsies showed columnar alterations, columnar cell lesions of the breast, were 1.78-fold more likely to develop an invasive breast cancer [odds ratio (OR) 1.78, 95% confidence interval (CI) 1.19-2.65] after adjusting for age at biopsy, biopsy year, and overall impression. Columnar alterations were not found to be significantly associated with risk of developing ductal carcinoma in situ (DCIS) among African American women [OR 1.53, 95% CI 0.83-2.82]. Next, to identify molecular markers associated with columnar alterations in benign breast lesions, we performed gene expression analyses on biopsy tissues from 27 African American women that subsequently developed an invasive breast cancer. Transcriptional profiling of these lesions identified differentially expressed genes significantly associated with columnar alterations, including ankyrin repeat domain 30A (ANKRD30A). ANKRD30A, also known as NY-BR-1, is a mammary tissue-specific differentiation antigen that is overexpressed in breast cancers. Increased expression of ANKRD30A in benign breast lesions with columnar alterations may be indicative of subsequent breast cancer development. Taken together, novel molecular markers, including ANKRD30A, and ethnicity can lead to better risk assessment and earlier diagnosis of breast cancer. Citation Format: Andreana N. Holowatyj, Rouba Ali-Fehmi, Julie J. Ruterbusch, Eman Abdulfatah, Vishakha Pardeshi, Woodlyne Roquiz, Baraa Alosh, Sudeshna Bandyopadhyay, Derek Radisky, Michele L. Cote. Ankyrin repeat domain 30A as a novel molecular marker of columnar alterations in benign breast disease and subsequent breast cancer in African American women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-378.