Estrogen receptor α in cancer associated fibroblasts suppresses prostate cancer invasion via reducing CCL5, IL6 and macrophage infiltration in the tumor microenvironment

Stromal E2/ERα signals negatively-regulate the PCa invasion. CAF.ERα(-) or ERα(+) cells were treated with vehicle, E2 (10 nM) or/and ICI182,780 (10 μM) and co-cultured with macrophages for 48 hr. CMs were collected and added to 24-well plates and the PCa cells (C4-2) were seeded into inserted transwells pre-coated with matrigel. After 48 hr of incubation, invaded PCa cells were counted and compared, and quantitation data is shown below the images

The Roles of Estrogen Receptors in the Bladder Cancer Development

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pathology and Laboratory Medicine, 2013.Early studies documented the existence of sexual dimorphism in bladder cancer occurrence and progression with higher bladder cancer incidence in males than females. However, the progression of bladder cancer after diagnosis is more rapid in females than males. These contrasting differences could be due to the differential effects of female hormones-estrogens, and their binding receptors including ERα and ERβ on the bladder cancer incidence and progression. Results from recent studies using various in vitro cell lines and in vivo mouse models demonstrate differential roles of ERs in cancer initiation and progression such that ERα suppresses bladder cancer initiation and invasion whereas ERβ promotes bladder cancer initiation and progression. Mechanistic studies indicate ERα and ERβ may act through modulation of the AKT activity/pathway or DNA replication complex, respectively, to influence bladder cancer progression. Targeting ER signaling pathways using various selective ER subtype modulators may lead to the development of new therapeutic approaches to control bladder cancer progression

Targeting newly identified ERβ/TGF‐β1/SMAD3 signals with the FDA‐approved anti‐estrogen Faslodex or an ERβ selective antagonist in renal cell carcinoma

Renal cell carcinoma (RCC) has the third highest mortality rate among urological tumors, and 20–30% of RCC patients present with metastatic RCC at the time of diagnosis. Although recent studies have indicated that estrogen receptor β (ERβ) could play promoting roles in RCC progression, the detailed mechanisms remain to be clarified. In the present study, we found that expression of ERβ, but not ERα, increases with tumor stage and grade, and also observed that modification of ERβ signals using estrogens/anti‐estrogens, shRNA knockdown of ERβ and overexpression of ERβ using ectopic cDNA affects RCC cell proliferation, migration and invasion. Mechanism analysis revealed that ERβ can promote RCC cell invasion via an increase in transforming growth factor β1 (TGF‐β1)/SMAD3 signals, and interrupting TGF‐β1/SMAD3 signals with a TGFβR1 inhibitor can reverse/block ERβ‐increased RCC cell migration. Importantly, preclinical analyses using in vivo mouse models of RCC revealed that targeting of this newly identified ERβ/TGF‐β1/SMAD3 pathway with either the FDA‐approved anti‐estrogen ICI182,780 (Faslodex) or a selective ERβ antagonist 4‐[2‐phenyl‐5,7 bis(trifluoromethyl)pyrazolo[1,5‐a]pyrimidin‐3‐yl]phenol can significantly reduce RCC tumor growth and invasion, which may be suitable as the basis for novel therapies to more effectively suppress metastatic RCC