Estrogen stimulates female cancer progression by inducing myeloid-derived suppressive cells: investigations on pregnant and non-pregnant experimental models

Abstract

Objective To investigate the clinical implications of 17β-estradiol (E2) in estrogen receptor α (ERα)-negative female cancer progression as well as the underlying biological mechanisms. Methods Clinical data from 306 locally-advanced cervical cancer (stage IIB-IVA) patients were analyzed in order to investigate the relationships between age, serum E2 levels, and treatment outcomes. Clinical samples, ERα-negative cervical and breast cancer cell lines, and mouse xenograft models of cervical and breast cancers were employed in order to elucidate the mechanisms responsible for the E2- and pregnancy-mediated progression of cervical and breast cancers, with a focus on the role of myeloid-derived suppressor cells (MDSC). Results Younger patients with elevated E2 levels showed significantly shorter progression-free survival ( P = 0.040) and overall survival ( P = 0.039). The exogenous E2 treatment stimulated the mobilization of MDSC from bone marrow and directly augmented their suppressive activities, leading to the progression of ERα-negative cervical and breast cancers. The co-administration of an anti-Gr-1 neutralizing antibody with E2 prevented the E2-mediated induction of MDSC, and attenuated E2-mediated tumor growth in cervical and breast cancer xenografts. Significantly increased MDSC numbers and enhanced tumor growth were observed during pregnancy in mice with cervical or breast cancer. Significantly increased MDSC numbers were also observed during pregnancy in cervical cancer patients. Conclusions E2 facilitates the progression of ERα-negative cervical or breast cancer under non-pregnant and pregnant conditions by inducing MDSC. MDSC inhibition therapy may have therapeutic efficacy in premenopausal or pregnant female cancer patients.

Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

“…In this regard, E2 promoted the growth of ER negative cervical and breast tumor xenografts in both pregnant and non-pregnant mice by inducing MDSCs (137). Moreover, addition of an anti-Gr-1 neutralizing antibody prevented E2 induction of MDSCs and attenuated tumor growth in these models (137). Together these studies provide evidence of regulation of MDSC biology by E2 in multiple solid tumor models, however this has been largely unexplored in lung cancer.…”

“…These studies have important implications for the consideration of estrogenic effects that are completely independent of tumoral ER status and a role for estrogen antagonists regardless of the ER status of the tumor. An MDSC focused analysis of 306 Stage IIB-IVA cervical cancer patients demonstrated that pregnant patients exhibiting high levels of serum E2 also had high levels of mobilized MDSCs (137). This observation was further evaluated in pregnant and non-pregnant mouse models of breast and cervical cancers.…”

“…This observation was further evaluated in pregnant and non-pregnant mouse models of breast and cervical cancers. In this regard, E2 promoted the growth of ER negative cervical and breast tumor xenografts in both pregnant and non-pregnant mice by inducing MDSCs (137). Moreover, addition of an anti-Gr-1 neutralizing antibody prevented E2 induction of MDSCs and attenuated tumor growth in these models (137).…”

The role of myeloid-derived suppressor cells in endometrial cancer displaying systemic inflammatory response: clinical and preclinical investigations

“…A T cell proliferation assay was conducted as reported previously. 23 A 24-well plate was coated with 1 μg/well of anti-CD3e antibody. CD8+ T cells were purified from the spleen of a Balb/c mouse using T-cell isolation columns (R&D systems, Minneapolis, MN) in accordance with the manufacturer's instructions and labeled with carboxyfluorescein succinimidyl ester (CFSE).…”

Estrogen Receptors and Ubiquitin Proteasome System: Mutual Regulation

“…They play an important role in prenatal and postnatal development [13]. The participation of estrogens in pathology is wide-ranging, including in cardiovascular and gastrointestinal diseases [14][15][16][17] as well as cancer [18,19]. The reception of estrogens is very important for the transmission of the estrogen signal and the realization of the effects of hormones.…”