RESUMEN
Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63+TCF7+ myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63+TCF7+ myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression.
Asunto(s)
Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Carcinoma Ductal de Mama/metabolismo , Mutación/genética , Animales , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal de Mama/genética , Línea Celular Tumoral , Proliferación Celular/genética , Proliferación Celular/fisiología , Femenino , Técnica del Anticuerpo Fluorescente , Mutación de Línea Germinal/genética , Humanos , Inmunohistoquímica , Ratones , Factor 1 de Transcripción de Linfocitos T/genética , Factor 1 de Transcripción de Linfocitos T/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression.Significance: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1098-115. ©2017 AACR.See related commentary by Speiser and Verdeil, p. 1062This article is highlighted in the In This Issue feature, p. 1047.
Asunto(s)
Neoplasias de la Mama/inmunología , Carcinoma Ductal de Mama/inmunología , Carcinoma Intraductal no Infiltrante/inmunología , Perfilación de la Expresión Génica/métodos , Linfocitos T/inmunología , Antígeno B7-H1/genética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Complejo CD3/genética , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Antígenos Comunes de Leucocito/genética , Receptor ErbB-2/genética , Microambiente TumoralRESUMEN
PURPOSE: Radial scar and radial sclerosis (RS) are considered benign breast lesions with proliferative features. There is sparse literature on frequency of cancer upgrade in these patients without atypical features found on image-guided needle biopsy. This study retrospectively reviews cases of isolated RS diagnosed on needle biopsy and evaluates the cancer upgrade after subsequent surgical excision. METHODS: We conducted a retrospective cross-sectional study of cases with an isolated RS diagnosis based on needle biopsy and subsequent surgical pathology among all patients between January 1, 2009 and December 31, 2013. Patients with concomitant atypia, lobular carcinoma in situ on core biopsy, complete excision of very small RS with needle biopsy, and radiology-pathology discordance were excluded. An upgrade from the needle biopsy of RS was defined as surgical excision pathology that revealed ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), and/or invasive lobular carcinoma (ILC). RESULTS: 10,921 image-guided needle biopsy pathology reports were collected and 88 patients (0.81 %) were identified as having isolated RS. Of these 88 patients, 63 (72 %) underwent excision. The upgrade rate to cancer on subsequent surgical excision was 1.59 % (1/63) for DCIS; 0 % (0/63) for IDC; and 0 % (0/63) ILC. Twenty-five patients who did not undergo surgical excision had stable imaging studies with mean (±SD) 26 (±20) months follow up. CONCLUSIONS: Isolated radial scar on needle biopsy may not warrant routine surgical excision given relatively low cancer upgrade rates. Advancement in breast imaging, pathology and multidisciplinary approaches to care may effectively guide non-surgical management of RS.
