Figure 8

Summary of the opposing autocrine/paracrine effects of the progesterone metabolites, 5αP and 3αHP, in a stylized ER/PR-negative human breast cell. Evidence presented here shows that a high concentration of 5αP relative to 3αHP, in the microenvironment, promotes initiation and growth of ER/PR-negative human breast cell tumors, whereas a higher concentration of 3αHP, relative to 5αP, suppresses tumorigenesis and promotes normalcy. Progesterone is converted to 3αHP and 5αP in breast cells. Tumorigenic and tumor cells convert more progesterone to 5αP and less to 3αHP than do normal cells. The steroids, being lipophylic, are able to pass out of cells and result in a concentration buildup in the microenvironment. The result is a significant increase in the 5αP-to-3αHP concentration ratio in the microenvironment of tumorigenic cells and within tumorous tissues in comparison with normal (nontumorous) breasts. 3αHP and 5αP bind to specific receptors on the plasma membrane linked to signaling pathways involving PKC, phospholipase C, and Ca²⁺ mobilization (3αHP) and MAPK/Erk1/2 (5αP) and to modulators of gene expression. The cancer-inhibiting actions of 3αHP result in decreased proliferation and detachment of cells, increased apoptosis, and suppression of tumor initiation and growth. The cancer-promoting actions of 5αP have the opposite effects and result in stimulation of tumorigenesis and tumor growth. The evidence suggests that high concentrations of 5αP relative to 3αHP in the microenvironment will promote progression toward neoplasia and tumorigenesis, whereas a low 5αP-to-3αHP concentration ratio favors maintenance of the normal state.