Disruption of the function of tumor suppressor proteins occasionally can be dependent on their subcellular localization. In about 40% of the breast cancer tissues, p53 is found in the cytoplasm as opposed to the nucleus, where it resides in normal breast cells. This means that the regulation of subcellular location of p53 is an important mechanism in controlling its function. The transport factors required for the nuclear export of p53 and the mechanisms of their nuclear export have been extensively characterized. However, little is known about the mechanism of nuclear import of p53. p53 contains putative nuclear localization signals (NLSs) which would interact with a nuclear transport factor, importin ␣. In this report we demonstrate that importin ␣ binds to NLSI in p53 and mediates the nuclear import of p53. Reverse transcriptase-polymerase chain reaction and sequencing analyses showed that a truncated importin ␣ deleted the region encoding the putative NLS-binding domain of p53, suggesting that it could not bind to NLSs of p53 proteins. Binding of importin ␣ to p53 was confirmed by using yeast two-hybrid assay. When expressed in CHO-K1 cells, the truncated importin ␣ predominantly localized to the cytoplasm. In truncated importin ␣ expressing cells, p53 preferentially localized to cytoplasmic sites as well. A significant increase in the p21 waf1/cip1 mRNA level and induction of apoptosis were also observed in importin ␣ overexpressing cells. These results strongly suggest that importin ␣ functions as a component of the NLS receptor for p53 and mediates nuclear import of p53.p53 is a tumor suppressor gene and various p53 gene mutations are found in over 50% of all human cancers (1). Although inactivation of tumor suppressor proteins is generally thought to originate in their genetic mutations, disruption of their function can occasionally be independent of such mutations. Moll et al. (2) have reported that about 37% out of 27 samples of breast cancer tissues showed cytoplasmic localization of wild-type p53, resulting in inhibition of normal p53 function (2). Nuclear exclusion of wild-type p53 has also been reported in neuroblastoma and colon carcinoma cells (3, 4). In another study, wild-type p53 was located in the cytoplasm of human cervical carcinoma cell lines with integrated human papillomavirus-18 or -16 (5). In colon carcinoma, cytoplasmic accumulation of p53 correlates with unfavorable prognosis (4). These data indicate that the regulation of p53 subcellular location is an important mechanism in controlling p53 function.In eukaryotic cells, the nucleus is separated from the cytoplasm by the nuclear envelope. This spatial segregation requires a nuclear transport system to correctly import or export nuclear components at the proper time. The prototype of the nuclear transport signal is the classical nuclear localization signal (NLS), 1 and nuclear import of proteins bearing an NLS is dependent on two cellular factors termed importin ␣ and importin ␤ (6 -11). The initial cytoplasmic event in NLS-dependent...

Breast cancer is the most common type of cancer in women, and approximately 70% of all breast cancer patients use endocrine therapy, such as estrogen receptor modulators and aromatase inhibitors. In particular, triple-negative breast cancer (TNBC) remains a major threat due to the lack of targeted treatment options and poor clinical outcomes. Here, we found that GPR110 was highly expressed in TNBC and GPR110 plays a key role in TNBC progression by engaging the RAS signaling pathway (via Gαs activation). High expression of GPR110 promoted EMT and CSC phenotypes in breast cancer. Consequently, our study highlights the critical role of GPR110 as a therapeutic target and inhibition of GPR110 could provide a therapeutic strategy for the treatment of TNBC patients.

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