PGRMC1 in animal breast cancer tissue and blood is associated with increased tumor growth with norethisterone in contrast to progesterone and dydrogesterone: four-arm randomized placebo-controlled xenograft study

Abstract

Progesterone receptor membrane component 1 (PGRMC1) is mediating strong breast cancer cell proliferation induced by certain synthetic progestogens which we have shown within already published in vitro studies. Aim was now to use an animal model, to compare tumor growth using progesterone and its isomer dydrogesterone with norethisterone, which elicited in our in vitro studies the strongest proliferating effect. For the first time, we wanted to investigate if growth can be correlated both with blood concentrations and tissue expression of PGRMC1 to identify if PGRMC1 could be a new tumor marker. Prospective, randomized, blinded, placebo-controlled four-arm study (45–50 days); PGRMC1-transfected or empty-vector T47D- and MCF7-xenotransplants were each treated with estradiol (E2) +placebo; E2 + progesterone; E2 + norethisterone; E2 + dydrogesterone; blood PGRMC1 assessed by a novel ELISA, tissue expression by immunohistochemistry. PGRMC1-transfected tumors further increased with E2 + norethisterone but not with E2-dydrogesterone or E2-progesterone. In both PGRMC1-xenograft groups (T47D, MCF7) with E2/norethisterone, the blood concentrations and tissue expression of PGRMC1 were higher than in all other 14 groups (p < .05), with positive significant correlation between blood PGRMCI concentrations and tissue PGRMC1 expression. In the presence of PGRMC1, certain progestogens could increase the growth of breast tumor, which now also should be tested in clinical studies.

摘要

在我们已发表的体外研究中发现孕激素受体膜组分1(PGRMC1)介导某些人工合成的孕激素诱导的乳腺癌细胞的强烈增殖。本研究的目的是利用动物模型, 比较黄体酮及其异构体地屈孕酮和炔诺酮对肿瘤生长的影响, 炔诺酮是我们在体外研究中发现的增殖效应最强的。这是我们首次研究肿瘤生长是否与PGRMC1的血液浓度和组织表达有关, 以确定PGRMC1是否可能成为一种新的肿瘤标记物。前瞻性、随机化、盲法、安慰剂对照的四臂研究(45-50天)；转染PGRMC1或空载体T47D和MCF7的异种移植物分别给予雌二醇(E2)＋安慰剂、雌二醇(E2)＋黄体酮、雌二醇＋炔诺酮、雌二醇＋地屈孕酮；用新的ELISA法检测血PGRMC1, 用免疫组化法检测组织中PGRMC1的表达。转染PGRMC1的肿瘤在雌二醇-炔诺酮作用下进一步增殖, 而在雌二醇-地屈孕酮或雌二醇-黄体酮作用下未见进一步增殖。在E2 + NET的PGRMC1-异种移植组（T47D, MCF7）中, PGRMC1的血液浓度和组织表达均高于其他14组(p<0.05), 血液PGRMCI浓度与组织PGRMC1表达呈显著正相关。在PGRMC1存在的情况下, 某些孕激素可以促进乳腺肿瘤的生长, 这一点现在还需要在临床研究中进行验证。

Keywords:

• Mouse xenograft model
• breast-tumor growth
• progestogens
• blood PGRMC1
• tissue PGRMC1

Acknowledgments

The authors thank Prof. Xingming Li from Capital Medical University, Department of Statistics, who helped us with the data analysis.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by National Natural Science Foundation of China [81671411]; the first batch of Beijing maternal and child health specialist demonstration units ‘menopausal health specialist’ (2018/01–2020/12) Beijing Natural Science Foundation [Grant no. 7162062] Beijing Nova Program Interdisciplinary Cooperation Projects [Grant no. Z161100004916045]