Androgens induce divergent proliferative responses in human breast cancer cell lines

Birrell, Stephen N.; Bentel, Jacqueline M.; Hickey, Theresa E.; Ricciardelli, Carmela; Weger, Martin; Horsfall, Debbie; Tilley, Wayne D.

doi:10.1016/0960-0760(95)00005-k

Cited by 224 publications

(174 citation statements)

References 24 publications

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“…Similarly, the testosterone metabolite DHT was shown by Birrell et al to inhibit the growth of some breast cancer cell lines, but induce the growth of others [7]. Anti-androgens demonstrated mixed ability to inhibit the effects of DHT on growth, and this was attributed to the potential activity of un-indentified DHT metabolites [7]. Macedo et al later showed that DHT is growth-inhibitory in MCF-7 cells under low-estrogen conditions, and that this effect was mediated by the androgen receptor [1].…”

Section: Discussionmentioning

confidence: 86%

“…A considerable amount of work has been done over the years studying the effects of androgens on the proliferation of breast cancer cells [1,[7][8][9][10][11][12]. The literature is, however, somewhat confusing, with conflicting data coming from relatively similar experimental systems.…”

Section: Discussionmentioning

confidence: 99%

“…For example, 30 years ago we demonstrated that under serum-free conditions, androgens stimulate thymidine incorporation in breast cancer cell lines apparently through the androgen receptor [8,12]. Similarly, the testosterone metabolite DHT was shown by Birrell et al to inhibit the growth of some breast cancer cell lines, but induce the growth of others [7]. Anti-androgens demonstrated mixed ability to inhibit the effects of DHT on growth, and this was attributed to the potential activity of un-indentified DHT metabolites [7].…”

Section: Discussionmentioning

confidence: 99%

“…We were therefore interested in the possibility that androgens and/or their downstream metabolites might play a role in resistance to AI therapy. A number of studies of the effects of androgens on breast cancer cells have been published, with the majority focusing on the effects of testosterone (TS) and 5α-dihydrotestosterone (DHT) on breast cancer growth [1,[7][8][9][10][11][12]. Little is known, however, about the effects of these compounds on breast cancer cell growth under conditions of profound estrogen deprivation, similar to conditions found in women treated with AIs.…”

Section: Introductionmentioning

confidence: 99%

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The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

Sikora

Cordero

Larios

et al. 2008

Breast Cancer Res Treat

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The aromatase inhibitors (AIs) are used to treat estrogen receptor-positive (ER+) breast tumors in post-menopausal women, and function by blocking the conversion of adrenal androgens to estrogens by the enzyme CYP19 aromatase. Breast cancer patients receiving AI therapy have circulating estrogen levels below the level of detection; however, androgen concentrations remain unchanged. We were interested in studying the effects of androgens on breast cancer cell proliferation under profound estrogen-deprived conditions. Using in vitro models of estrogen-dependent breast cancer cell growth we show that the androgens testosterone and 5α-dihydrotestosterone induce the growth of MCF-7, T47D and BT-474 cells in the absence of estrogen. Furthermore, we demonstrate that under profound estrogen-deprived conditions these breast cancer cells up-regulate steroidogenic enzymes that can metabolize androgens to estrogens. Lastly, we found that the downstream metabolite of 5α-dihydrotestosterone, 5α-androstane-3β,17β-diol (3βAdiol), is estrogenic in breast cancer cells, and induces growth and ER-signaling via activation of ERα. In conclusion, our results show that breast cancer cells deprived of estrogen up-regulate steroidogenic enzymes and metabolize androgens to estrogen-like steroids. The generation of estrogen-like steroids represents a potential mechanism of resistance to aromatase inhibitors.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

Sikora

Cordero

Larios

et al. 2008

Breast Cancer Res Treat

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show abstract

“…Androgen receptor has been implicated in breast tumorigenesis; however, delineating its precise function has proven difficult, with androgen receptor-mediated androgenic effects shown to both stimulate and inhibit growth of breast cancer cells. 15,16 The significance of androgen receptor in human breast cancer is further emphasized by the recent finding that it can be targeted in ER-negative breast tumors. 17 Some studies demonstrated that loss of androgen receptor expression is associated with early-onset, high nuclear-grade, and negative ER, PR and HER2 expression status in breast tumors.…”

mentioning

confidence: 99%

Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer

et al. 2014

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Treatment of triple-negative invasive breast cancers, defined by the absence of estrogen and progesterone receptors and c-erbB2 expression, remains challenging. Androgen receptor, a member of the nuclear receptor superfamily that is involved in signaling pathways regulating cell proliferation, has been implicated in breast tumorigenesis. We immunohistochemically examined the expression of androgen receptor, basal markers (CK14, 34bE12) and EGFR in 699 triple-negative invasive breast cancers in tissue microarrays using the streptavidin-biotin method, and correlated the findings with clinical outcome. Positive androgen receptor expression was defined as staining of 1% or more of tumor cell nuclei. Survival outcomes were estimated with the Kaplan-Meier method and compared between groups with log-rank statistics. Cox proportional hazards models were used to determine the effect of androgen receptor on survival outcomes. Immunohistochemical positivity was observed in 38% of tumors, with the proportion of stained tumor cells ranging from 1 to 95% (mean 29%, median 10%). Androgen receptor expression was inversely associated with histologic grade and mitotic score. CK14, 34bE12 and EGFR confirmed 85% of cases to be basal-like, without significant association of basal-like phenotype with androgen receptor expression. Disease-free survival was significantly better in androgen receptor-positive triple-negative breast cancer, with a trend for improved overall survival. Decreased recurrence likelihood in both triple-negative and basal-like tumors (hazard ratio, 0.704; 95% confidence intervals, 0.498-0.994; P ¼ 0.0464; and hazard ratio, 0.675; 95% confidence intervals, 0.468-0.974; P ¼ 0.0355, respectively) was noted within 5 years of diagnosis but not thereafter. Our study suggests that loss of androgen receptor in triple-negative breast cancers augurs a worse prognosis, including those with basal-like features. More work in elucidating its relationship with mechanisms of progression, as well as trials of targeted treatment for androgen receptor-expressing triple-negative tumors, needs to be performed.

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Flame retardance of montmorillonite/rubber composites

Huang

Zhao

et al. 2007

J of Applied Polymer Sci

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The effect of dispersion of clay in rubber on the mechanical properties and flame retardance of rubber/ montmorillonite (MMT) nanocomposites and rubber/MMT microcomposites were investigated in the present article, and the results were compared with the performance of silica reinforced rubber composites. Cone calorimeter test and limiting oxygen index test were employed to evaluate the flame retardance. From the results, it could be seen that the rubber/MMT nanocomposites always possessed the best flame retardance, such as lower peak heat release rate and higher fire performance index value. In addition, the rubber/MMT nanocomposites also showed better mechanical properties than the pure rubber and the other composites, especially in tear strength. With the rubber/ silica composites, as expected, the silica could appropriately endow the rubber with flame retardance.

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Androgens induce divergent proliferative responses in human breast cancer cell lines

Cited by 224 publications

References 24 publications

The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer

Flame retardance of montmorillonite/rubber composites

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