Inhibition of mammary tumor growth by estrogens: is there a specific role for estrogen receptors alpha and beta?

Abstract

To evaluate the extent to which each estrogen receptor (ER) subtype contributes to the stimulation or to the inhibition of mammary tumor growth, we evaluated the effects of specific agonists in MC4-L2 cells, which are stimulated by 17β-estradiol (E(2)), and in mammary carcinomas of the MPA mouse breast cancer model, which are inhibited by E(2). Both express ERα and ERβ. In MC4-L2 cells, 4,4',4"-(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT; ERα agonist) and (4-hydroxy-phenyl)-propionitrile (DPN; ERβ agonist) stimulated cell proliferation, whereas the opposite occurred in C4-HI primary cultures. The inhibitory effect was associated with a decrease in ERα and cyclin D1 expression and an increase in progesterone receptor (PR) expression as well as in the Bax/Bcl-xl ratio. In vivo, mice carrying C4-HI or 32-2-HI tumors were treated with E(2), PPT or DPN (3 mg/kg/day) or with vehicle. PPT and DPN inhibited tumor size, as did E(2), during the first 72 h. After a few days, DPN-treated tumors started to grow again, while PPT-treated tumors remained quiescent for a longer period of time. A pronounced decrease in the mitotic index and an increase in the apoptotic index was associated with tumor regression. All treated tumors showed: (a) an increase in integrin α6 and Bax expression, (b) an increased stromal laminin redistribution, and (c) a decrease in ERα, Bcl-xl and Bcl-2 expression (P < 0.001). Apoptosis-inducing factor (Aif) expression was increased in DPN-treated tumors, while active caspase 9 was up-regulated in PPT-treated mice, demonstrating the involvement of the intrinsic apoptotic pathway in estrogen-induced regression in this model. In conclusion, our data indicate that although there may be some preferences for activation pathways by the different agonists, the stimulatory or inhibitory effects triggered by estrogens are cell-context dependent rather than ER isoform dependent.

The effectiveness of nano chemotherapeutic particles combined with mifepristone depends on the PR isoform ratio in preclinical models of breast cancer

“…Our results are in agreement with those reported by Nakasone et al ., who found that free doxorubicin accumulates in cells flanking tumor vessels in two different transgenic mouse models [35]. In support of the remodeling hypothesis, we also demonstrated that estrogen treatment, which also induces tumor regression in this model [36], is also able to increase the therapeutic effect of these chemotherapeutic drugs (data not shown). Other drugs have also been proposed to alter the tumor microenvironment such as hialuronidase that improved the access of PEG-LD in osteosarcoma xenografts [37], or losartan, an angiotensin receptor inhibitor that inhibits the synthesis of collagen type I present in desmoplastic tumors [38].…”

Responsiveness to PI3K and MEK Inhibitors in Breast Cancer. Use of a 3D Culture System to Study Pathways Related to Hormone Independence in Mice

“…We have previously shown that when C4-HI tumors are exposed to estrogens they regress, and this phenomenon correlates with a down regulation of ERα levels in the epithelial compartment [53]. During tumor regression, there is a reduction in proliferative and antiapoptotic molecules such as cyclin D1 and Bcl-XL, respectively; and an increase in BAX release, leading to the activation of the intrinsic apoptotic mechanism of caspase 9.…”

“…During tumor regression, there is a reduction in proliferative and antiapoptotic molecules such as cyclin D1 and Bcl-XL, respectively; and an increase in BAX release, leading to the activation of the intrinsic apoptotic mechanism of caspase 9. Finally, reduced ERα levels correlates with an increase in stromal laminin-1 redistribution with a concomitant increase in integrin α6, which contributes to enhance tumor regression by differentiation [53]. In the light of the experiments shown here where LY294002 causes ERα down regulation both in C4-HD and C4-HI tumors (Figure 6) but tumor regression, by apoptosis and differentiation, only in C4-HI tumors (Figure 1), we postulate that AKT regulates C4-HI tumor growth, at least in part, by keeping ERα levels.…”

MPA-induced gene expression and stromal and parenchymal gene expression profiles in luminal murine mammary carcinomas with different hormonal requirements

“…There is no human situation that exactly mimics the growth of C4-HD tumors, because they grow only under continuous exogenous hormone administration. However, we believe that the C4-HI tumor may be compared with luminal human breast carcinomas that highly express ER and PR because they have a ductal histology, they express keratins 8 and 18 (see Supplementary data file 2), they grow in untreated mice and they are ER-and PR-dependent (the blockage of either of these receptors inhibits tumor growth) [37,38]. In addition, C4-HI tumors metastasize in axillary lymph nodes similarly to most human breast cancers [12,39], and they are able to acquire hormone resistance [38].…”