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Erα Mediates Estrogen-Induced Expression of the Breast Cancer Metastasis Suppressor Gene Brms1

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Erα Mediates Estrogen-Induced Expression of the Breast Cancer Metastasis Suppressor Gene Brms1 ERΑ MEDIATES ESTROGEN-INDUCED EXPRESSION OF THE BREAST CANCER METASTASIS SUPPRESSOR GENE BRMS1 The Texas Tech community has made this publication openly available. Please share how this access benefits you. Your story matters to us. Citation Ma, H., & Gollahon, L. (2016). ERα Mediates Estrogen-Induced Expression of the Breast Cancer Metastasis Suppressor Gene BRMS1. International Journal of Molecular Sciences, 17(2), 158. MDPI AG. Retrieved from http://dx.doi.org/10.3390/ijms17020158 Citable Link http://hdl.handle.net/2346/66800 Terms of Use CC-BY 4.0 Title page template design credit to Harvard DASH. International Journal of Molecular Sciences Article ERα Mediates Estrogen-Induced Expression of the Breast Cancer Metastasis Suppressor Gene BRMS1 Hongtao Ma and Lauren S. Gollahon * Department of Biological Sciences, Texas Tech University, 2901 Main St. Suite 108, Lubbock, TX 79409, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-806-834-3287; Fax: +1-806-742-2963 Academic Editor: William Chi-shing Cho Received: 16 December 2015; Accepted: 18 January 2016; Published: 26 January 2016 Abstract: Recently, estrogen has been reported as putatively inhibiting cancer cell invasion and motility. This information is in direct contrast to the paradigm of estrogen as a tumor promoter. However, data suggests that the effects of estrogen are modulated by the receptor isoform with which it interacts. In order to gain a clearer understanding of the role of estrogen in potentially suppressing breast cancer metastasis, we investigated the regulation of estrogen and its receptor on the downstream target gene, breast cancer metastasis suppressor 1 (BRMS1) in MCF-7, SKBR3, TTU-1 and MDA-MB-231 breast cancer cells. Our results showed that estrogen increased the transcription and expression of BRMS1 in the ERα positive breast cancer cell line, MCF-7. Additionally, the ERα specific agonist PPT also induced the transcription and expression of BRMS1. However, the two remaining estrogen receptor (ER) subtype agonists had no effect on BRMS1 expression. In order to further examine the influence of ERα on BRMS1 expression, ERα expression was knocked down using siRNA (siERα). Western blot analysis showed that siERα reduced estrogen-induced and PPT-induced BRMS1 expression. In summary, this study demonstrates estrogen, via its α receptor, positively regulates the expression of BRMS1, providing new insight into a potential inhibitory effect of estrogen on metastasis suppression. Keywords: breast cancer; metastasis; estrogen; estrogen receptor; BRMS1 1. Introduction Breast cancer is the leading female cancer in the United States and the leading cause of cancer-associated death in women. One of the risk factors associated with breast cancer development is a woman’s lifetime exposure to estrogen [1,2]. Estrogen performs its function through its estrogen receptor (ER) in target cells [3]. However, prior (and current) studies gauge the effect of estrogen on the ER in general; not delineated based on the different subtypes. Evidence is slowly emerging that demonstrate distinctions in the functions of ER subtypes with respect to cancer [4]. Our study looked specifically at the effect of the estrogen on the known ER subtypes to determine if there was a correlation with activation of a putative down-stream target involved in metastasis. Two types of estrogen receptors exist. The nuclear estrogen receptor (nER) is a member of the nuclear hormone family of intracellular receptors. nERs exist as two isoforms, α and β. The estrogen G protein coupled receptor GPR30 is a cytoplasmic receptor, which is predominantly associated with the endoplasmic reticulum [5,6]. Upon estrogen binding, several sites along the nER undergo phosphorylation and subsequent conformational changes freeing the receptor from the Hsp90 aggregate. At this point, the activated receptor subunits dimerize and bind to the estrogen response element (ERE) in the promoter regions of target genes in the nucleus [7–9]. In addition, the nER may also regulate gene expression by binding to transcriptional complexes on other promoter sites, Int. J. Mol. Sci. 2016, 17, 158; doi:10.3390/ijms17020158 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2016, 17, 158 2 of 15 e.g., Sp1 or AP1 [10–15]. In contrast, upon estrogen binding, the membrane-bound estrogen receptor Int. J. Mol. Sci. 2016, 17, 158 2 of 15 GPR30 activates G proteins, which in turn activate adenyl cyclases, Src, and SphK. These kinases mediateSp1 subsequentor AP1 [10–15]. transcriptional In contrast, responsesupon estrogen [16– binding,18]. the membrane-bound estrogen receptor ItGPR30 is well activates known G that proteins, estrogen which promotes in turn activate the proliferation adenyl cyclases, of ER positiveSrc, and SphK. cancer These cells bothkinasesin vivo and inmediate vitro [19 subsequent–25]. In contrast, transcriptional other studiesresponses have [16–18]. reported estrogen-induced inhibition of cancer cell invasion andIt is motilitywell known [23 that,26– estrogen28]. However, promotes the the mechanism proliferation of of this ER inhibitory positive cancer effect cells remains both in unknown. vivo Recentand data in vitro suggest [19–25]. that In the contrast, ER may other mediate studies transcription have reported of estrogen-induced metastasis-associated inhibition genes, of cancer e.g., nm23, cell invasion and motility [23,26–28]. However, the mechanism of this inhibitory effect remains KAI1, KiSS1, and MTA [29–33]. Breast cancer metastasis suppressor 1 (BRMS1), a known metastasis unknown. Recent data suggest that the ER may mediate transcription of metastasis-associated genes, suppressore.g., nm23, gene, KAI1, has KiSS1, been shownand MTA to [29–33]. suppress Breast metastasis cancer metastasis of a variety suppressor of tumor 1 (BRMS1), cell lines, a known including breast,metastasis melanoma, suppressor bladder, gene, ovarian has been and shown lung [to34 supp–38].ress Several metastasis studies of a have variety indicated of tumor a cell possible lines, link betweenincluding the ER breast, and melanoma, BRMS1. One bladder, study, ovarian involving and lung 161 breast[34–38]. carcinoma Several studies specimens, have indicated showed a that the levelpossible of BRMS1link between mRNA the expressionER and BRMS1. was One marginally study, involving higher in161 ER breastα-positive carcinoma group specimens, than in the ERα-negativeshowed that group the [level39]. Anof BRMS1 analysis mRNA of 238 expression tissue samples was marginally by microarray higher showed in ERα-positive a trend forgroup BRMS1 towardsthan a in positive the ERα association-negative group with [39]. the ERAn [analysis40]. Frolova of 238et tissue al. [41 samples] found by that microarray nuclear showed expression a of BRMS1trend was for positively BRMS1 towards correlated a positive with expression association of with ER. ER-negativethe ER [40]. Frolova breast cancers et al. [41] were found significantly that morenuclear likely thanexpression ER-positive of BRMS1 cancers was positively to have low correl BRMS1,ated with and expression loss of nuclear of ER. BRMS1ER-negative was associatedbreast cancers were significantly more likely than ER-positive cancers to have low BRMS1, and loss of with ER-negative cancers. Based on this information, we investigated whether BRMS1 expression nuclear BRMS1 was associated with ER-negative cancers. Based on this information, we investigated in breastwhether cancer BRMS1 cells expression was mediated in breast through cancer cells a specific was mediated estrogen through receptor a specific in response estrogen receptor to estrogen. Our resultsin response demonstrate to estrogen. that Our BRMS1 results expressiondemonstrate isth upregulatedat BRMS1 expression by estrogen is upregulated stimulation by estrogen through its ERα receptor.stimulation through its ERα receptor. 2. Results2. Results 2.1. ER2.1. Subtype ER Subtype Expression Expression in MCF-7,in MCF-7, TTU-1, TTU-1, MDA-MB-231, MDA-MB-231, and and SKBR3 SKBR3 Cell Cell Lines Lines In orderIn order to test to thetest effects the effects of ER of influence ER influence on BRMS1, on BRMS1, the ERthe subtypeER subtype expression expression in MCF-7,in MCF-7, TTU-1, MDA-MB-231,TTU-1, MDA-MB-231, and SKBR3 and cell SKBR3 lines wascell lines investigated was investigated by Western by Western analysis. analysis. Results Results showed showed that the expressionthat the of expression the ER subtype of thewas ER dependentsubtype was upon depende thent characteristics upon the characteristics of the individual of the cancerindividual cell line (Figurecancer1). MCF-7 cell line cells, (Figure (histopathologically 1). MCF-7 cells, (histopathologically ER+) expressed ER+) all three expressed ER subtypes, all three ER ER subtypes,α, ERβ, and ERα, ERβ, and GPR30. Neither TTU-1 (histopathologically ER−) nor MDA-MB-231 GPR30. Neither TTU-1 (histopathologically ER´) nor MDA-MB-231 (histopathologically ER´) cells (histopathologically ER−) cells expressed ERα. SKBR3 cells (histopathologically ER−) only expressed α ´ expressedGPR30 ER (Figure. SKBR3 1). Based cells (histopathologicallyon protein expression ERlevels,) only MCF-7, expressed TTU-1 and GPR30 SKBR3 (Figure were1 ).further Based on proteinanalyzed. expression levels, MCF-7, TTU-1 and SKBR3 were further analyzed. Figure 1. Protein expression levels for breast cancer cells demonstrating different ER subtypes. Figure 1. Protein expression levels for breast cancer cells demonstrating different ER subtypes.
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