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CDCA8 is a key mediator of estrogen-stimulated cell proliferation in breast T cancer cells
a Department of Breast Surgery, The People's Hospital of Cangzhou, Cangzhou 061000, Hebei, China
b Department of General Surgery, The People's Hospital of Cangzhou, Cangzhou 061000, Hebei, China
Endocrine therapy is eﬀective in the early stage of breast cancer treatment, and most tumor cells will gain the ability to proliferate under residual amounts of estrogen, which will cause the recurrence of the disease. The role of cell division cycle associated 8 (CDCA8) in Estradiol (E2)-stimulated breast cancer cells growth is investigated in this research. CDCA8 showed higher mRNA expression in E2-stimulated MCF7 and T47D cells, and such an increase could also be observed in tumor samples. CDCA8 shRNA inhibited the survival and growth detected by cell number and colony formation, while promoted FG-4592 G1 phase arrest determined with flow cytometry, which coordinated with a decrease in E2-induced molecules, namely Cyclin D1 (CCND1), B-Cell CLL/Lymphoma 2 (BCL2), and an increase in apoptosis-related molecules, such as cyclin-dependent kinase inhibitor 1a (P21) and cyclin-dependent kinase inhibitor 1b (P27). Kaplan-Meier plot analysis indicated that higher CDCA8 expression was positively associated with poor prognosis with a probability lower than 0.4 at the five-year interval (p = 0.035). All of these suggest that CDCA8 is a key mediator of estrogen-stimulated breast cancer cell growth and survival, which can be utilized as a novel target in breast cancer treatment.
It is evaluated that approximately 70% of breast cancers are hor-mone-dependent and estrogen receptor-positive (ER-positive) (Bates et al., 2018; Emens, 2018). A great post-surgical survival improvement, a decrease in relapse, and a reduction in the incidence of contralateral cancers can be attributed to the implement of adjuvant systemic therapy, especially to those ER-positive patients in the early phase, who have received endocrine therapy or combined with cytotoxic therapy (Tyson et al., 2011; Wazir et al., 2018). ER expression is regarded as the main indicator of potential response to endocrine therapy. However, such treatments are often followed by primary and acquired resistance to endocrine manipulations, for most tumor cells will acquire the ability to proliferate under estrogen depletion with the up-regulated ER ex-pression, which will make the cells more hypersensitive to residual amounts of estrogen and cause the recurrence of the disease. The pos-sible mechanisms involved in this phenomenon are only allusively in-vestigated (Jones, 2001; Anurag et al., 2018; Hartmaier et al., 2018).
Borealin/Dasra B, also known as cell division cycle associated 8 (CDCA8), is an integral part of the chromosomal passenger complex (CPC), which will function at the centromere to ensure the correct chromosome alignment and segregation and act as a key regulator of mitosis (Sandrine et al., 2007; Waal et al., 2012; Sanne et al., 2015). Such an eﬀect is essential for the genome transmission during cell di-vision. CDCA8 can function as a possible oncogene that may be up-regulated in multiple types of cancer, which will give rise to the sur-vival and malignant of various cancers, such as gastric cancer, bladder cancer, cutaneous melanoma, and lung cancer (Daigo et al., 2008; Bi et al., 2018; Ci et al., 2019).
CDCA8 expression is screened in the Oncomine and the Cancer Cell Line Encyclopedia (CCLE) databases and Gene Expression-Based Outcome for Breast Cancer Online (GOBO), which is testified to be associated with the survival of breast cancer patient (Phan et al., 2018). Whether CDCA8 is involved in the residual amounts of Estradiol (E2)-induced breast tumor cells proliferation and survival is investigated in this study, which will point a novel way to deal with the recurrence of
Abbreviations: CDCA8, cell division cycle associated 8; E2, Estradiol; P21, cyclin-dependent kinase inhibitor 1a; P27, cyclin-dependent kinase inhibitor 1b; CCND1, Cyclin D1; BCL2, B-cell leukemia/lymphoma 2; CPC, chromosomal passenger complex; ER, estrogen receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; CCLE, Cancer Cell Line Encyclopedia; GOBO, Gene Expression-Based Outcome for Breast Cancer Online