Abstract
Pax transactivation domain interacting protein (PTIP) associated protein 1, PA1, was a newly found protein participating in the modulation of transactivity of nuclear receptor super family members such as estrogen receptor (ER), androgen receptor (AR) and glucocorticoid receptor (GR). Breast cancer is one of the most life threatening diseases for women and has tight association with estrogen and ER. This study was performed to understand the function of PA1 in breast cancer. The expression of PA1 had been evaluated in a total of 344 primary invasive breast cancer samples and examined the relationship with clinical output, relapse free survival (RFS), breast cancer-specific survival (BCSS). PA1 expression was observed in both nucleus and cytoplasm, however, appeared mainly in nuclear. PA1 nuclear expression was correlated with postmenopausal (P = 0.0097), smaller tumor size (P = 0.0025), negative Ki67 (P = 0.02), positive AR (P = 0.049) and positive ERβ (P = 0.0020). Kaplan–Meier analysis demonstrated PA1 nuclear positive cases seemed to have a longer survival than negative ones for RFS (P = 0.023) but not for BCSS (P = 0.23). In the Cox hazards model, PA1 nuclear protein expression proved to be a significant prognostic univariate parameter for RFS (P = 0.03), but not for BCSS (P = 0.20). In addition, for those patients without lymphnode metastasis PA1 was found to be an independent prognostic factor for RFS (P = 0.025), which was verified by univariate and multivariate analyses. These investigations suggested PA1 expression could be a potential prognostic indicator for RFS in breast cancer.
Highlights
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths among American women, and has been identified as a public health priority in the United States
PA1 with Pax transactivation domain interacting protein (PTIP) was found to participate in DNA damage response via ring finer protein 8 (RNF8), E3 ubiquitin-protein ligase, dependent pathway and was required for cell survival after DNA damage [25]
It was discovered that PA1 modulates transcriptional activity of nuclear receptor in a receptor-specific manner, which demonstrated to be an estrogen receptor (ER) activator, glucocorticoid receptor (GR) suppressor, and plays a role in estrogen stimulating G1/S cell cycle progression [15,16]
Summary
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths among American women, and has been identified as a public health priority in the United States. Extensive searching for the modulation factors is of urgent importance for the endocrine therapy of breast cancer patients. Our work in this field with others is highly clinically relevant, and admired by both patients and clinicians, and led to the discovery that several cofactors, such as nuclear receptor corepressor 1 (NCOR1), histone deacetylase 1 (HDAC1), and histone deacetylase 6 (HDAC6), which have clinical importance to enhance the accuracy of prediction of endocrine therapy responsiveness and prognosis [8,9,10]
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