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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

Moderate aromatase expression rendered ZR-75-1 cells tumorigenic without estrogen supplementation.A. Luc-GFP expressing ZR-75-1/Aro Cl.10 and TT1 cells (2x106) were inoculated into the inguinal mammary fat pads of 5-wk-old female nude mice. The tumor sizes were measured with a caliper in two dimensions. Tumor volumes were calculated with the equation V = (LxW2)/2, where L is length and W is width of a tumor. Values are mean±SEM of 10 tumors in 5 mice. B. The representative images (fluorescence on the left and bioluminescence on the right) C. The mice with growing tumors were divided into two groups and treated with vehicle or letrozole at 10 μg/mouse/day.
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pone.0121136.g005: Moderate aromatase expression rendered ZR-75-1 cells tumorigenic without estrogen supplementation.A. Luc-GFP expressing ZR-75-1/Aro Cl.10 and TT1 cells (2x106) were inoculated into the inguinal mammary fat pads of 5-wk-old female nude mice. The tumor sizes were measured with a caliper in two dimensions. Tumor volumes were calculated with the equation V = (LxW2)/2, where L is length and W is width of a tumor. Values are mean±SEM of 10 tumors in 5 mice. B. The representative images (fluorescence on the left and bioluminescence on the right) C. The mice with growing tumors were divided into two groups and treated with vehicle or letrozole at 10 μg/mouse/day.

Mentions: To investigate the role of aromatase and potential intracrine estrogen signaling in promoting tumorigenesis, we implanted the Cl.10 and TT1 cells orthotopically into female athymic mice. The control ZR-75-1 cells were used as a control. Notably, a moderate expression level of ectopic aromatase caused Cl.10 and TT1 cells to become tumorigenic with no exogenous estrogen supplementation after three weeks of inoculation (Fig. 5A) whereas the control ZR-75-1 cells did not form any tumor. However, no significant differences in the tumor size were observed between Cl.10 group and TT1 group. Because the cells stably express both GFP and luciferase, the orthotopic tumors were also detected by fluorescence and bioluminescence imaging (Fig. 5B).


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)

Moderate aromatase expression rendered ZR-75-1 cells tumorigenic without estrogen supplementation.A. Luc-GFP expressing ZR-75-1/Aro Cl.10 and TT1 cells (2x106) were inoculated into the inguinal mammary fat pads of 5-wk-old female nude mice. The tumor sizes were measured with a caliper in two dimensions. Tumor volumes were calculated with the equation V = (LxW2)/2, where L is length and W is width of a tumor. Values are mean±SEM of 10 tumors in 5 mice. B. The representative images (fluorescence on the left and bioluminescence on the right) C. The mice with growing tumors were divided into two groups and treated with vehicle or letrozole at 10 μg/mouse/day.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383596&req=5

pone.0121136.g005: Moderate aromatase expression rendered ZR-75-1 cells tumorigenic without estrogen supplementation.A. Luc-GFP expressing ZR-75-1/Aro Cl.10 and TT1 cells (2x106) were inoculated into the inguinal mammary fat pads of 5-wk-old female nude mice. The tumor sizes were measured with a caliper in two dimensions. Tumor volumes were calculated with the equation V = (LxW2)/2, where L is length and W is width of a tumor. Values are mean±SEM of 10 tumors in 5 mice. B. The representative images (fluorescence on the left and bioluminescence on the right) C. The mice with growing tumors were divided into two groups and treated with vehicle or letrozole at 10 μg/mouse/day.
Mentions: To investigate the role of aromatase and potential intracrine estrogen signaling in promoting tumorigenesis, we implanted the Cl.10 and TT1 cells orthotopically into female athymic mice. The control ZR-75-1 cells were used as a control. Notably, a moderate expression level of ectopic aromatase caused Cl.10 and TT1 cells to become tumorigenic with no exogenous estrogen supplementation after three weeks of inoculation (Fig. 5A) whereas the control ZR-75-1 cells did not form any tumor. However, no significant differences in the tumor size were observed between Cl.10 group and TT1 group. Because the cells stably express both GFP and luciferase, the orthotopic tumors were also detected by fluorescence and bioluminescence imaging (Fig. 5B).

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