Induction of apoptosis in mammary gland by a pure anti-estrogen ICI 182780

Abstract

The antiestrogen, ICI 182780 (ICI) proves to be clinically useful for the treatment of estrogen receptor positive breast tumours. We report the assessment of the in vivo and in vitro effects of ICI on apoptosis of breast epithelial cells. In vivo, administration of rats with ICI for 3 weeks resulted in a reduction in the size of the lobular structures with the rate of mammary epithelial apoptosis equivalent to 10, 35 and 45% on treatment with 1, 1.5 and 2 mg ICI per kg body weight, respectively. Concomitantly, these treatment led to a 2.0-, 2.2- and 2.5-fold increase in Bax. Similar elevations were also observed in Bad levels which increased 1.7-, 2.6- and 2.7-fold respectively in the ICI treatment as compared to controls. This also resulted in a dose dependent decrease in Bcl-2 and Bcl-xL protein expressions. Growth inhibition and induction of apoptosis were also observed in the MCF-7 cells following in vitro treatment with ICI. This is closely associated with [1] the down-regulation of Bcl-2 and Bcl-xL proteins and [2] upregulation of Bax and Bad, whose gene products are known to be involved the regulation of apoptosis in mammalian cells. Stable over-expression of Bcl-2 resulted in protection of MCF-7 cells from apoptosis and growth inhibitory effects of ICI. Conversely, reduction of Bcl-2 by antisense transfection make MCF-7 cells more sensitive to ICI-induced growth inhibition and apoptosis. These findings suggest that modulation of Bax, Bcl-xL, Bcl-2 and Bad proteins by ICI may be, in part, responsible for the anti-proliferative and apoptotic effect of ICI seen clinically and in animal models.

Age-Related Reduction in Estrogen Receptor–Mediated Mechanisms of Vascular Relaxation in Female Spontaneously Hypertensive Rats

“…Also, ICI-182780 is a selective ER antagonist. 41,42 The observation that the vascular effects of E2 were abolished in tissues treated with the ER antagonist ICI-182780 lends support to the contention that they are ER mediated. The decreased E2-induced inhibition of vascular contraction in aging rats could then be owing to reduction in the amount of ER or in the E2/ER-mediated mechanisms of vascular relaxation.…”

Midregion PTHrP regulates Rip1 and caspase expression in MDA-MB231 breast cancer cells

“…In addition, although the data obtained put in evidence a certain stability of the expression levels for most of the genes coding for apoptosis modulators, nonetheless the cytotoxic effect triggered by midregion PTHrP on MDA-MB231 could see the involvement of some pro-apoptotic factors, such as Bad and Bcl-xS, whose up-regulation was found to promote cell death in different breast cancer cell lines, including MDA-MB231 [50][51][52][53][54]; on the other hand, alteration of Bad transcription or mRNA stability was reported to be an early and potentially-critic regulation point of cellular response to stress or drug-induced injury [55]. It is worth-mentioning that, taking previous and present data into consideration, the cytotoxic effect of midregion PTHrP appears to display some programmed cell death-related aspects although it cannot be considered as an example of ''classical'' apoptosis [see 56,57] for the previously-reported absence of ''ladder-like'' electrophoretic pattern of DNA fragmentation and negativity to the apoptosis-discriminating ApopTag cytochemical assay [32], and for the lack of phosphatydilserine externalization (unpublished results), at all examined times of PTHrP treatment.…”

Dysregulation of microRNA expression in acquired endocrine-resistant breast cancer.

“…However, BCL2 mRNA could not be detected in L Y2 cells, whether EtOH or 4-0HT treated (data not shown). As expected based on our previous data and the work of others [268,312], E2 increased BCL2 mRNA in MCF-7 cells. 4-0HT had no significant effect on BCL2 mRNA expression in MCF-7 cells.…”