Abstract
Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium-associated RING Chromosome 1), a novel gene encoding a member of the TRIM (tripartite motif) subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer. Suppression subtractive hybridization identified DEAR1 as a novel gene mapping to a region of high-frequency loss of heterozygosity (LOH) in a number of histologically diverse human cancers within Chromosome 1p35.1. In the breast epithelium, DEAR1 expression is limited to the ductal and glandular epithelium and is down-regulated in transition to ductal carcinoma in situ (DCIS), an early histologic stage in breast tumorigenesis. DEAR1 missense mutations and homozygous deletion (HD) were discovered in breast cancer cell lines and tumor samples. Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D) basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo. Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs) recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation. Furthermore, immunohistochemical staining of a tissue microarray from a cohort of 123 young female breast cancer patients with a 20-year follow-up indicated that in early-onset breast cancer, DEAR1 expression serves as an independent predictor of local recurrence-free survival and correlates significantly with strong family history of breast cancer and the triple-negative phenotype (ER(-), PR(-), HER-2(-)) of breast cancers with poor prognosis. Our data provide compelling evidence for the genetic alteration and loss of expression of DEAR1 in breast cancer, for the functional role of DEAR1 in the dominant regulation of acinar morphogenesis in 3D culture, and for the potential utility of an immunohistochemical assay for DEAR1 expression as an independent prognostic marker for stratification of early-onset disease.
Highlights
Breast cancer is the most common cause of cancer-related death in women with an early onset of the disease (#45 years of age) [1]
In screening cDNAs obtained from a suppression subtractive hybridization library (Figure S1 and Text S1), we identified a 700 bp partial cDNA with significant sequence similarity to a family of RING finger proteins (3.9610218) and that mapped by fluorescence in situ hybridization (FISH) to one of the Chromosome 1p genomic intervals with loss of heterozygosity (LOH) in breast cancer within Chromosome 1p34-35
DEAR1 is composed of five exons encoding a 475 amino acid protein with a predicted tripartite sequence motif associated with the RBCC (RING-B-box-CoiledCoil)/tripartite motif (TRIM) subfamily of RING finger proteins with PRY and SPRY domains present within the carboxyl terminus (Figure 1B) [29,30,31,32,33,34,35]
Summary
Breast cancer is the most common cause of cancer-related death in women with an early onset of the disease (#45 years of age) [1]. In order to stratify early-onset cancers, the genetic mechanisms that underlie breast cancer in young women must first be elucidated. Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. More than one million women discover that they have breast cancer This type of cancer begins when cells in the breast that line the milk-producing glands or the tubes that take the milk to the nipples (glandular and ductal epithelial cells, respectively) acquire genetic changes that allow them to grow uncontrollably and to move around the body (metastasize). In the US, for example, nearly 90% of affected women are still alive five years after their diagnosis
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