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Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells.

Mukhopadhyay KD, Liu Z, Bandyopadhyay A, Kirma NB, Tekmal RR, Wang S, Sun LZ - PLoS ONE (2015)

Bottom Line: This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women.Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival.The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, United States of America.

ABSTRACT
In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERα) positive breast cancer cell survival and growth. This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERα positive breast cancer cells were cultured in suspension. Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERα positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERα breast cancer cells by suppressing anoikis.

No MeSH data available.


Related in: MedlinePlus

Aromatase expression levels in ERα+ breast cancer cell lines.A. mRNA levels of aromatase detected with RT-PCR in ERα+ breast cancer cell lines (ZR-75-1, ZR-75-1/Aro Cl.10, ZR-75-1/Aro-Clone10-TT1, T47D, CAMA-1 BT474). ZR: ZR-75-1 control cells stably transfected with an empty vector; Cl.10: a clone of ZR-75-1 cells stably transfected with an aromatase expression vector; TT1: cell line derived from a xenograft tumor formed by ZR-75-1/Aro Cl.10 cells in female nude mouse. B. Western immunoblotting of aromatase in various ERα+ cell lines. C. Aromatase enzyme activity in the extracts of ZR-75-1, ZR-75-1/Aro Cl.10, MCF-7 and MCF-7/Aro cell lines.
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pone.0121136.g001: Aromatase expression levels in ERα+ breast cancer cell lines.A. mRNA levels of aromatase detected with RT-PCR in ERα+ breast cancer cell lines (ZR-75-1, ZR-75-1/Aro Cl.10, ZR-75-1/Aro-Clone10-TT1, T47D, CAMA-1 BT474). ZR: ZR-75-1 control cells stably transfected with an empty vector; Cl.10: a clone of ZR-75-1 cells stably transfected with an aromatase expression vector; TT1: cell line derived from a xenograft tumor formed by ZR-75-1/Aro Cl.10 cells in female nude mouse. B. Western immunoblotting of aromatase in various ERα+ cell lines. C. Aromatase enzyme activity in the extracts of ZR-75-1, ZR-75-1/Aro Cl.10, MCF-7 and MCF-7/Aro cell lines.

Mentions: We found that human ERα+ breast cancer cell lines (ZR-75-1, CAMA1, T47D and BT474) express variable, but detectable levels of aromatase transcripts by real time RT PCR (Fig. 1A), and ZR-75-1 and CAMA1 cell lines also express detectable aromatase protein levels with Western immunoblotting (Fig. 1B). On the other hand, aromatase-transfected ZR-75-1 cells, Cl.10 and TT1 (see Materials and Methods for their generation), expressed aromatase mRNA and protein at a higher level than the breast cancer cell lines, but lower than previously reported [14] in aromatase transfected MCF-7 cells. Consistent with the expression levels, the aromatase activity assay showed that aromatase-transfected ZR-75-1 cells (Cl.10) had an intermediate level of aromatase enzyme activity when compared to control cells and MCF-7/Aro cells (Fig. 1C).


Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells.

Mukhopadhyay KD, Liu Z, Bandyopadhyay A, Kirma NB, Tekmal RR, Wang S, Sun LZ - PLoS ONE (2015)

Aromatase expression levels in ERα+ breast cancer cell lines.A. mRNA levels of aromatase detected with RT-PCR in ERα+ breast cancer cell lines (ZR-75-1, ZR-75-1/Aro Cl.10, ZR-75-1/Aro-Clone10-TT1, T47D, CAMA-1 BT474). ZR: ZR-75-1 control cells stably transfected with an empty vector; Cl.10: a clone of ZR-75-1 cells stably transfected with an aromatase expression vector; TT1: cell line derived from a xenograft tumor formed by ZR-75-1/Aro Cl.10 cells in female nude mouse. B. Western immunoblotting of aromatase in various ERα+ cell lines. C. Aromatase enzyme activity in the extracts of ZR-75-1, ZR-75-1/Aro Cl.10, MCF-7 and MCF-7/Aro cell lines.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4383596&req=5

pone.0121136.g001: Aromatase expression levels in ERα+ breast cancer cell lines.A. mRNA levels of aromatase detected with RT-PCR in ERα+ breast cancer cell lines (ZR-75-1, ZR-75-1/Aro Cl.10, ZR-75-1/Aro-Clone10-TT1, T47D, CAMA-1 BT474). ZR: ZR-75-1 control cells stably transfected with an empty vector; Cl.10: a clone of ZR-75-1 cells stably transfected with an aromatase expression vector; TT1: cell line derived from a xenograft tumor formed by ZR-75-1/Aro Cl.10 cells in female nude mouse. B. Western immunoblotting of aromatase in various ERα+ cell lines. C. Aromatase enzyme activity in the extracts of ZR-75-1, ZR-75-1/Aro Cl.10, MCF-7 and MCF-7/Aro cell lines.
Mentions: We found that human ERα+ breast cancer cell lines (ZR-75-1, CAMA1, T47D and BT474) express variable, but detectable levels of aromatase transcripts by real time RT PCR (Fig. 1A), and ZR-75-1 and CAMA1 cell lines also express detectable aromatase protein levels with Western immunoblotting (Fig. 1B). On the other hand, aromatase-transfected ZR-75-1 cells, Cl.10 and TT1 (see Materials and Methods for their generation), expressed aromatase mRNA and protein at a higher level than the breast cancer cell lines, but lower than previously reported [14] in aromatase transfected MCF-7 cells. Consistent with the expression levels, the aromatase activity assay showed that aromatase-transfected ZR-75-1 cells (Cl.10) had an intermediate level of aromatase enzyme activity when compared to control cells and MCF-7/Aro cells (Fig. 1C).

Bottom Line: This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women.Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival.The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, United States of America.

ABSTRACT
In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERα) positive breast cancer cell survival and growth. This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERα positive breast cancer cells were cultured in suspension. Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERα positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERα breast cancer cells by suppressing anoikis.

No MeSH data available.


Related in: MedlinePlus