Polyamine involvement in basal and estradiol-stimulated insulin-like growth factor I secretion and action in breast cancer cells in culture

The hormone dependency of the MCF-7 breast cancer cell line, while extensively tested in liquid culture, has not been previously evaluated under conditions of anchorage-independent growth in serum-free media. Using the soft agar clonogenic assay, we demonstrate that physiologically relevant concentrations of estradiol (E2), progesterone (Pg), and prolactin (PRL) similarly stimulated MCF-7 cell colony formation in the absence of serum. Addition of an anti-insulin-like growth factor-I (IGF-I) antibody inhibited E2- and Pg-stimulated growth, while PRL action was not affected. Similar results were obtained with an anti-IGF-I receptor antibody, except that its inhibitory effect on Pg-induced colony formation was modest and not statistically significant. Administration of either an anti-transforming growth factor-alpha (TGF-alpha) antibody or an anti-epidermal growth factor (EGF) receptor antibody similarly inhibited E2-stimulated MCF-7 cell growth in soft agar, while neither antibody influenced Pg or PRL effects. Addition of TGF-beta 1, -beta 2, -beta 3 similarly suppressed MCF-7 cell colony formation in a dose dependent manner to a degree comparable to that observed with 4-OH-tamoxifen (4-OH-T). Furthermore, the growth inhibitory effect of 4-OH-T was completely reversed by an anti-TGF-beta antibody. We conclude that IGFs and TGF-alpha are important mediators of E2-stimulated MCF-7 cell growth in soft agar. IGFs may also be playing a role in Pg action, while neither growth factor is involved in PRL-stimulated colony formation. Finally, TGF-beta appears to be an important mediator of antiestrogen-induced inhibition of tumor growth.

Section: Introductionmentioning

confidence: 99%

Growth factor involvement in the multihormonal regulation of MCF-7 breast cancer cell growth in soft agar

Manni

Wright

Buck

1991

“…Breast cancer cells have been shown to secrete these peptides in vitro [4][5][6][7][8], to contain high affinity membrane receptors for them [9,10], and to manifest a proliferative response following exogenous growth factor administration [4,11]. Furthermore, in hormone responsive breast cancer celt lines, growth factor production has been found to be hormonally regulated [4][5][6][7][8], although the role of these peptides as mediators of estradiol-stimulated tumor growth remains controversial [4,12,13].…”

Section: Rn Etindi Et Atmentioning

confidence: 99%

“…trisphosphate [Ins (1,4,5)P3], which releases intracellular calcium and 1,2 diacylglycerol (DAG), which activates protein kinase C (PKC) [1,2].…”

Section: Rn Etindi Et Atmentioning

confidence: 99%

The effects of TGF-α and 17β-estradiol on polyphosphoinositide metabolism in MCF-7 breast cancer cells

Etindi

Manni

Martel

1992

Self Cite

The mechanism by which transforming growth factor-alpha (TGF-alpha) stimulates breast cancer cell proliferation is largely unknown. Furthermore, its potential role as an autocrine effector of estradiol-17 beta (E2)-stimulated growth of hormone-dependent mammary tumors remains controversial. Transient changes in phosphatidylinositol (PI) turnover have been demonstrated in several tissues in response to growth factors. In these experiments, we tested the effects of TGF-alpha and E2 on PI metabolism in three MCF-7 breast cancer cell sublines (MCF-7B, MCF-7I, and MCF-7J). Although TGF-alpha was mitogenic in MCF-7I and MCF-7J cells, PI hydrolysis was stimulated by the growth factor only in the MCF-7I cells. In addition, the TGF-alpha effect was relatively modest, ranging from 23% to 42%. E2 effects on PI turnover were tested in the MCF-7B cells, which were the most sensitive to the proliferative effect of the hormone. E2 did not stimulate PI hydrolysis, whether or not the cells were labelled in the presence of the hormone. On the other hand, E2 did seem to stimulate de novo synthesis of phosphatidylinositol and induce activation of PI kinases. These results demonstrate that TGF-alpha-stimulated PI hydrolysis is modest and cell type dependent. At least under certain conditions, PI metabolism is not involved in the proliferative effects of TGF-alpha (MCF-7J) or E2 (MCF-7B). The role of increased PI synthesis in E2-stimulated MCF-7 cell growth remains to be established.

“…Since it has been suggested that polyamine compounds may play a role in the proliferation of breast cancer cells by interacting with the IGF family of proteins [31], Kim et al studied the effects of the polyamine synthesis inhibitor difluoromethylornithine (DFMO) on IGFBP synthesis and secretion in two HBCCLs. They found that DFMO treatment was associated with decreased IGFBP-t and IGFBP-2 mRNA expression in MDA-MB-231 and MCF-7, respectively.…”

Section: Regulation Of Igfbp Expression In Human Breast Cancer Cellsmentioning

confidence: 99%

The insulin-like growth factor binding proteins (IGFBPs) in human breast cancer

Figueroa

Yee

1992

Several lines of evidence suggest that IGFs are important regulators of breast cancer cell growth. Unlike other growth factors, the IGFs interact with specific binding proteins in all extracellular fluids. To date, six different IGFBPs have been cloned, although their exact physiological function is not understood. Experimental evidence accumulated over the past few years suggests that IGFBPs could function as modulators of IGF actions in a variety of systems. This includes breast cancer, since several groups have demonstrated the production of IGFBPs by human breast cancer cells. We have found that the pattern of expression of these binding proteins is heterogeneous and varies depending on the breast cancer cell ER status. We have also shown that estrogen is capable of regulating the expression of certain IGFBPs in MCF-7 cells. Specifically, estradiol enhanced the expression of IGFBP 2, 4, and 5, and decreased that of IGFBP-3 in this cell line. Since the IGFBPs can modulate IGF actions in different experimental systems, we and others have studied their potential role as inhibitors of IGF-induced mitogenesis in breast cancer cells. We have demonstrated that purified IGFBP-1 neutralized IGF-dependent growth of MCF-7 cells in a reversible manner. These results suggest that the IGFBPs might be used to inhibit IGF-mediated breast cancer proliferation.