Aromatase & CRPC cells

[pjoshea13]

New study below [1].

ERα is the alpha estrogen receptor [ER]. In healthy prostates it is found in stromal cells. ERbeta is found in healthy epithelial cells, but there is a switch to ERα as PCa develops. ERα promotes growth.

Aromatase [CYP19A1] is the enzyme that converts testosterone [T] to estradiol [E2]. It is not found in healthy epithelial cells.

CD44+ cells are PCa stem cells.

MMP12 is a member of the matrix metalloproteinase (MMP) family, involved in the breakdown of the extracellular matrix, which holds cells in place. To become metastatic, cells must break free of the matrix.

"We found that aromatase expression was significantly increased in CRPC tissues and cell lines. In some prostate cancer cell lines, aromatase was predominantly expressed in CD44+ subsets."

"Bicalutamide {Casodex} treatment significantly increased aromatase expression, and CYP19A1 expression positively correlated with estrogen responses and epithelial-mesenchymal transition."

"Taken together, our findings indicated that increased endogenous estrogen, catalyzed by elevated aromatase levels, enhanced MMP12 expression via ERα, participated in CRPC progression and promoted tumour metastasis."

"Thus, aromatase represents a potential novel therapeutic target for CRPC."

Some of us here use Arimidex to control E2 levels. This should not be required while on ADT, since there is not enough T to produce significant E2. In fact, a low-dose E2 patch might be required for bone health.

However, it looks as though some men might benefit from Arimidex to inhibit intracrine production of E2.

However, maintaining bone integrity is essential. Might a low-dose E2 patch be safe?

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/314...

Cancer Lett. 2019 Sep 6. pii: S0304-3835(19)30465-3. doi: 10.1016/j.canlet.2019.09.001. [Epub ahead of print]

Aromatase-induced endogenous estrogen promotes tumour metastasis through estrogen receptor-α/matrix metalloproteinase 12 axis activation in castration-resistant prostate cancer.

Liang Z1, Cao J1, Tian L1, Shen Y1, Yang X1, Lin Q1, Zhang R1, Liu H2, Du X1, Shi J3, Zhang J4.

Author information

1

Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China.

2

Shanghai First People's Hospital Shanghai Jiaotong University, Shanghai, 200080, China.

3

Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China. Electronic address: [e-mail].

4

Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China. Electronic address: [e-mail].

Abstract

Castration-resistant prostate cancer (CRPC) following androgen deprivation therapy remains a major obstacle advanced prostate cancer management. Aromatase catalyzes estrogen from androgens, yet the role of aromatase-generated endogenous estrogen in CRPC is poorly understood. In this study, we assessed the expression and function of aromatase in CRPC. We found that aromatase expression was significantly increased in CRPC tissues and cell lines. In some prostate cancer cell lines, aromatase was predominantly expressed in CD44+ subsets. Bicalutamide treatment significantly increased aromatase expression, and CYP19A1 expression positively correlated with estrogen responses and epithelial-mesenchymal transition. Aromatase knockdown in PC3 cells reduced invasiveness and decreased metastasis-related gene expression. The aromatase inhibitor, letrozole, attenuated tumour metastasis in castrated PC3-xenograft mice. Mechanistically, aromatase-induced endogenous estrogen promoted estrogen receptor-α (ERα) binding to matrix metalloproteinase 12 (MMP12) promoter estrogen response element (ERE). MMP12 co-localized with CD44 on the cell membrane and MMP12 knockdown significantly reduced estradiol-induced PC3 invasion. Taken together, our findings indicated that increased endogenous estrogen, catalyzed by elevated aromatase levels, enhanced MMP12 expression via ERα, participated in CRPC progression and promoted tumour metastasis. Thus, aromatase represents a potential novel therapeutic target for CRPC.

Copyright © 2019. Published by Elsevier B.V.

KEYWORDS:

CD44; CYP19A1; MMP12; androgen independence prostate cancer; endogenous estrogenic effects

PMID: 31499120 DOI: 10.1016/j.canlet.2019.09.001