Research Article: DEAR1 Is a Dominant Regulator of Acinar Morphogenesis and an Independent Predictor of Local Recurrence-Free Survival in Early-Onset Breast Cancer

Date Published: May 5, 2009

Publisher: Public Library of Science

Author(s): Steven T. Lott, Nanyue Chen, Dawn S. Chandler, Qifeng Yang, Luo Wang, Marivonne Rodriguez, Hongyan Xie, Seetharaman Balasenthil, Thomas A. Buchholz, Aysegul A. Sahin, Katrina Chaung, Baili Zhang, Shodimu-Emmanu Olufemi, Jinyun Chen, Henry Adams, Vimla Band, Adel K. El-Naggar, Marsha L. Frazier, Khandan Keyomarsi, Kelly K. Hunt, Subrata Sen, Bruce Haffty, Stephen M. Hewitt, Ralf Krahe, Ann McNeill Killary, John D. Minna

Abstract: Ann Killary and colleagues describe a new gene that is genetically altered in breast tumors, and that may provide a new breast cancer prognostic marker.

Partial Text: 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]. Although breast cancer occurs less frequently in young women than in older women, it is often associated with a poorer prognosis. Compared with older women, young women with breast cancer have decreased overall survival and disease-free survival rates, and a higher percentage of tumors with pathologic features reflective of aggressive disease [2]–[6]. In early onset breast cancers without nodal involvement, approximately one-fourth will recur up to 12 years postsurgery [6]. In addition, younger age is recognized as a risk factor for local–regional recurrence and for distant metastases after either breast conservation treatment or mastectomy [5],[6]. Biomarkers are urgently needed to identify young women who have an increased risk of breast cancer recurrence and would therefore benefit from heightened surveillance and adjuvant therapy. However, in order to stratify early-onset cancers, the genetic mechanisms that underlie breast cancer in young women must first be elucidated.

Herein we describe the identification of the novel gene DEAR1 and provide evidence for its role in the dominant regulation of acinar morphogenesis in three-dimensional culture. DEAR1 undergoes mutation and deletion in breast cancer. Furthermore, by complementation of a somatic tumor-derived missense mutation, wild-type DEAR1 restored acinar structures that, by size, polarity, and presence of luminal apoptosis, resembled normal mammary acini grown under similar conditions. Stable knockdown of DEAR1 in immortalized HMECs recapitulated the phenotype in 21MT cells with disruption of tissue architecture, loss of polarity, and lumen formation, indicating that DEAR1 is required for normal acinar morphogenesis in 3D culture. Together, these data define DEAR1 as a critical link between the control of tissue architecture via ECM remodeling and a tumor-specific mutational event in breast cancer.



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