Dataset Information

Increased expression of ASRGL1 in invasive ductal carcinoma and its association with estrogen-progesterone receptor status of tumors.

ABSTRACT:

Aims

Human asparaginase-like protein 1 (ASRGL1) is closely related to tumor growth. ASRGL1 can significantly promote cell proliferation and suppress apoptosis. To date, high levels of expression of ASRGL1 have been reported in various tumors, but the function of ASRGL1 in carcinogenesis is still not well understood. In this study, we aimed to immunohistochemically investigate the expression of ASRGL1 in non-neoplastic breast tissue and invasive ductal carcinoma.

Methods and results

ASRGL1 was evaluated immunohistochemically in 148 invasive ductal carcinomas and 105 nonneoplastic breast tissue samples to assess the impact on breast cancer development and its association with clinicopathologic features. ASRGL1 was observed positive in 63 (42.6%) and negative in 85 (57.4%) invasive ductal carcinoma. In nonneoplastic breast tissue, 24 (22.9%) cases were ASRGL1 positive and 81 (77.1%) were negative. A significant difference was observed between invasive ductal carcinoma and nonneoplastic breast tissue in terms of ASRGL1 expression, and ASRGL1 expression was increased in invasive ductal carcinoma (P = .001). Most estrogen receptor-negative tumors and progesterone receptor-negative tumors were also negative with ASRGL1 and the difference was significant (P = .006 and P = .001, respectively). The correlation between the ASRGL1 expression of the tumors and event-free survival or overall survival was not significant (P>.05).

Conclusions

ASRGL1 may play a role in increasing cell proliferation and breast cancer development. ASRGL-1 expression in breast cancer closely correlates with the hormone receptor status of the tumor. In breast cancer, ASRGL-1 expression does not contribute to predicting tumor behavior.

SUBMITTER: Eren Karanis MI

PROVIDER: S-EPMC8340146 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionOf the nearly 1.4 million new cases of breast cancer diagnosed each year, a large proportion is characterized as hormone receptor negative, lacking estrogen receptors (ER) and/or progesterone receptors (PR). Patients with receptor-negative tumors do not respond to current steroid hormone-based therapies and generally have significantly higher risk of recurrence and mortality compared with patients with tumors that are ER- and/or PR-positive. Previous in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines. Here in vivo studies were conducted to investigate the ability of 5αP and 3αHP to control initiation, growth, and regression of ER/PR-negative human breast cell tumors.MethodsER/PR-negative human breast cells (MDA-MB-231) were implanted into mammary fat pads of immunosuppressed mice, and the effects of 5αP and 3αHP treatments on tumor initiation, growth, suppression/regression, and histopathology were assessed in five separate experiments. Specific radioimmunoassays and gas chromatography-mass spectrometry were used to measure 5αP, 3αHP, and progesterone in mouse serum and tumors.ResultsOnset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. The levels of 5αP in tumors, regardless of treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP ratios were about fivefold higher than in serum, indicating significant changes in endogenous synthesis of these hormones in tumorous breast tissues.ConclusionsThe studies showed that estrogen/progesterone-insensitive breast tumors are sensitive to, and controlled by, the progesterone metabolites 5αP and 3αHP. Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions. The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress. The results provide the first hormonal theory to explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions. The findings suggest new diagnostics based on the relative levels of these hormones and new approaches to prevention and treatment of breast cancers based on regulating the levels and action mechanisms of anti- and pro-cancer progesterone metabolites.