Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin β1

CCN5 (cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed 5)/WISP-2 [WNT1 (wingless-type MMTV integration site family, member 1)-inducible signalling pathway protein 2] is an oestrogen-regulated member of the CCN family. CCN5 is a transcriptional repressor of genes associated with the EMT (epithelial–mesenchymal transition) and plays an important role in maintenance of the differentiated phenotype in ER (oestrogen receptor)-positive breast cancer cells. In contrast, CCN5 is undetectable in more aggressive ER-negative breast cancer cells. We now report that CCN5 is induced in ER-negative breast cancer cells such as MDA-MB-231 following glucocorticoid exposure, due to interaction of the endogenous glucocorticoid receptor with a functional glucocorticoid-response element in the CCN5 gene promoter. Glucocorticoid treatment of MDA-MB-231 cells is accompanied by morphological alterations, decreased invasiveness and attenuated expression of mesenchymal markers, including vimentin, cadherin 11 and ZEB1 (zinc finger E-box binding homeobox 1). Interestingly, glucocorticoid exposure did not increase CCN5 expression in ER-positive breast cancer cells, but rather down-regulated ER expression, thereby attenuating oestrogen pathway signalling. Taken together, our results indicate that glucocorticoid treatment of ER-negative breast cancer cells induces high levels of CCN5 expression and is accompanied by the appearance of a more differentiated and less invasive epithelial phenotype. These findings propose a novel therapeutic strategy for high-risk breast cancer patients.

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Fulvestrant-induced expression of erbB3 and erbB4 sensitizes ER-positive breast cancer cells to heregulins

Breast Cancer Research ◽

10.1186/bcr2510 ◽

2010 ◽

Vol 12 (S1) ◽

Cited By ~ 1

Author(s):

IR Hutcheson ◽

L Goddard ◽

JMW Gee ◽

D Barrow ◽

RI Nicholson

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Induced Expression ◽

Er Positive ◽

Positive Breast Cancer

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A Role for ER-Beta in the Effects of Low-Density Lipoprotein Cholesterol and 27-Hydroxycholesterol on Breast Cancer Progression: Involvement of the IGF Signalling Pathway?

Cells ◽

10.3390/cells11010094 ◽

2021 ◽

Vol 11 (1) ◽

pp. 94

Author(s):

Reham M. Mashat ◽

Hanna A. Zielinska ◽

Jeff M. P. Holly ◽

Claire M. Perks

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Oestrogen Receptor ◽

Breast Cancer Cells ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Migration And Invasion ◽

Low Density ◽

Igf I ◽

Positive Breast Cancer

Cholesterol—in particular, high levels of low-density lipoprotein (LDL) and its metabolite, 27-hydroxycholesterol (27-OHC)—is correlated with increases in the risks of breast cancer and obesity. Although the high expression of LDL/27-OHC has been reported in breast cancer, its effects and mechanism of action remain to be fully elucidated. In this study, we found that the effects of LDL on cell proliferation were mediated by the activation of the cytochrome P450 enzyme, sterol 27 hydroxylase, and cholesterol 27-hydroxylase (CYP27A1) in both ER-α-positive and ER-α-negative breast cancer cells. We found that treatment with 27-OHC only increased cell growth in oestrogen receptor-α (ER-α)-positive breast cancer cells in an ER-α-dependent manner, but, interestingly, the effects of 27-OHC on cell migration and invasion were independent of ER-α. Using ER-α-negative MDA-MB-231 cells, we found that 27-OHC similarly promoted cell invasion and migration, and this was mediated by oestrogen receptor β (ER-β). These results suggest that 27-OHC promotes breast cancer cell proliferation in ER-α-positive breast cancer cells via ER-α, but migration and invasion are mediated via ER-β in ER-α positive and negative cell lines. The addition of LDL/27OHC increased the production of IGF-I and the abundance of IGF-IR in TNBC. We further found that modulating ER-β using an agonist or antagonist increased or decreased, respectively, levels of the IGF-I and EGF receptors in TNBC. The inhibition of the insulin-like growth factor receptor blocked the effects of cholesterol on cell growth and the migration of TNBC. Using TCGA and METABRIC microarray expression data from invasive breast cancer carcinomas, we also observed that higher levels of ER-beta were associated with higher levels of IGF-IR. Thus, this study shows novel evidence that ER-β is central to the effects of LDL/27OHC on invasion, migration, and the IGF and EGF axes. Our data suggest that targeting ER-β in TNBC could be an alternative approach for downregulating IGF/EGF signalling and controlling the impact of LDL in breast cancer patients.

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Exploration of mechanisms of α-linolenic acid in reducing the growth of oestrogen receptor positive breast cancer cells (MCF-7)

Journal of Functional Foods ◽

10.1016/j.jff.2016.04.037 ◽

2016 ◽

Vol 24 ◽

pp. 513-519 ◽

Cited By ~ 3

Author(s):

Julie K. Mason-Ennis ◽

Lauren P. LeMay-Nedjelski ◽

Ashleigh K.A. Wiggins ◽

Lilian U. Thompson

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Linolenic Acid ◽

Oestrogen Receptor ◽

Breast Cancer Cells ◽

Mcf 7 ◽

Positive Breast Cancer

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Inducible upregulation of oestrogen receptor-β1 affects oestrogen and tamoxifen responsiveness in MCF7 human breast cancer cells

Journal of Molecular Endocrinology ◽

10.1677/jme.1.01688 ◽

2005 ◽

Vol 34 (2) ◽

pp. 553-566 ◽

Cited By ~ 48

Author(s):

L C Murphy ◽

B Peng ◽

A Lewis ◽

J R Davie ◽

E Leygue ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Oestrogen Receptor ◽

Breast Cancer Cells ◽

Breast Cancer Patients ◽

Growth Responses ◽

Over Expression ◽

Er Positive ◽

Positive Breast Cancer ◽

Tamoxifen Sensitivity

To investigate the effect of altered oestrogen receptor (ER)α and ERβ expression on oestrogen and anti-oestrogen action in breast cancer, we have stably expressed an inducible ERβ1 in MCF7 breast cancer cells. Stably expressing clones were isolated and over-expression of ERβ1 correlated with increased levels of specific radiolabelled oestradiol (E2) binding. Increased ERβ1 did not affect endogenous levels of ERα but increased progesterone receptor (PR) levels. Over-expression of ERβ1 reduced growth responses to E2 in contrast to little if any effect of over-expression of ERα. In oestrogen-replete conditions, over-expression of ERβ1 but not ERα reduced proliferation. Over-expression of ERβ1 did not result in anti-oestrogen resistance but was associated with increased sensitivity to 4-hydroxytamoxifen. Our results suggested that over-expression of ERβ1 in the presence of an endogenously expressed ERα was associated with tamoxifen sensitivity but may negatively modulate ERα-mediated growth. However, not all ERα activities were inhibited since endogenous PR expression was increased by both ERα and ERβ1 over-expression. These data paralleled those seen in some in vivo studies showing a relationship between PR and ERβ expression as well as ERβ expression and tamoxifen sensitivity of ER-positive breast cancer patients. These models are relevant and will be useful for dissecting the role of ERβ1 expression in ER-positive breast cancer.

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