Limits...
Local adipocytes enable estrogen-dependent breast cancer growth: Role of leptin and aromatase.

Liu E, Samad F, Mueller BM - Adipocyte (2013)

Bottom Line: Here we describe a unique animal model to study interactions between adipocytes and breast cancer cells in the tumor microenvironment.Our results suggest that local interactions between adipocytes and tumor cells are sufficient to promote the growth of hormone-dependent breast cancer.We also demonstrate that leptin signaling in adipocytes induces aromatase expression, expected to result in higher estrogen in the microenvironment thus enabling mammary tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Torrey Pines Institute for Molecular Studies; San Diego, CA USA.

ABSTRACT
The importance of the microenvironment in breast cancer growth and progression is becoming increasingly clear. Adipocytes are abundant in the mammary microenvironment, and recent studies show that adipocytes produce endocrine, inflammatory, and angiogenic factors that have tremendous potential to affect adjacent breast cancer cells. Yet, the extent to which local adipocyte function contributes to the pathogenesis of breast cancer is largely unexplored. Here we describe a unique animal model to study interactions between adipocytes and breast cancer cells in the tumor microenvironment. Our results suggest that local interactions between adipocytes and tumor cells are sufficient to promote the growth of hormone-dependent breast cancer. We also demonstrate that leptin signaling in adipocytes induces aromatase expression, expected to result in higher estrogen in the microenvironment thus enabling mammary tumorigenesis.

No MeSH data available.


Related in: MedlinePlus

Figure 4. Induction of aromatase expression by leptin. Aromatase mRNA expression in para-uterine fat pads from ob/ob (A) and wild-type C57BL/6 mice (B) 3 h after ip injection with saline (control), or leptin (10 μg; R&D Systems). (A and B) n = 6, mean ± SD; *P < 0.05 **P < 0.01. Gene expression was measured using real-time quantitative PCR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3756105&req=5

Figure 4: Figure 4. Induction of aromatase expression by leptin. Aromatase mRNA expression in para-uterine fat pads from ob/ob (A) and wild-type C57BL/6 mice (B) 3 h after ip injection with saline (control), or leptin (10 μg; R&D Systems). (A and B) n = 6, mean ± SD; *P < 0.05 **P < 0.01. Gene expression was measured using real-time quantitative PCR.

Mentions: Obese women have a higher risk for hormone-dependent breast cancer development, recurrence and death38,39 and obesity has also been found to hinder breast cancer treatment.40 To address the issue of aromatase expression in obesity we compared aromatase expression in the adipose tissue of lean and obese mice in a model of diet-induced obesity (DIO). Lean six-week-old female C57BL/6J mice were placed for 16 weeks on either a high fat diet (HFD; D12492; Research Diets) in which 60% of the total calories were derived from fat or a control low fat diet (LFD; D12450B) in which 10% of the total calories were derived from fat. The HFD induced obesity whereas LFD resulted in moderate age-appropriate weight gain. After 16 weeks para-uterine adipose tissues were removed, RNA was prepared and aromatase mRNA determined by real-time PCR. Aromatase mRNA was increased more than 45 fold in adipose tissues of HFD induced obese mice compared with LFD fed lean mice (Fig. 3B). HFD-induced obesity is a model that closely resembles human obesity including a marked increase in circulating leptin. Therefore the increase in aromatase expression in HFD mice could potentially be due to higher leptin levels. To address this question further we tested aromatase expression in leptin-deficient genetically obese ob/ob mice. Aromatase mRNA in the para-uterine adipose tissue of adult obese C57BL/6J ob/ob mice was significantly lower than in matched lean wild-type control mice (Fig. 3C), suggesting that leptin drives aromatase gene expression in adipose tissue. To further test this hypothesis, we injected mice with recombinant leptin and found that leptin increased aromatase expression in the adipose tissue of leptin-deficient ob/ob mice and also in the adipose tissue of lean mice (Fig. 4). Together our results not only demonstrate that leptin signaling in the adipose tissues increases aromatase expression, but also suggest that leptin and aromatase in the local tumor microenvironment play a crucial role in development and growth of hormone-dependent breast cancer. These findings provide a foundation to understanding the regulation of aromatase in adipose tissues in general and in the tumor microenvironment specifically and can provide a rationale for targeting the adipocyte leptin-aromatase axis in the prevention and/or treatment of hormone-dependent breast cancer.


Local adipocytes enable estrogen-dependent breast cancer growth: Role of leptin and aromatase.

Liu E, Samad F, Mueller BM - Adipocyte (2013)

Figure 4. Induction of aromatase expression by leptin. Aromatase mRNA expression in para-uterine fat pads from ob/ob (A) and wild-type C57BL/6 mice (B) 3 h after ip injection with saline (control), or leptin (10 μg; R&D Systems). (A and B) n = 6, mean ± SD; *P < 0.05 **P < 0.01. Gene expression was measured using real-time quantitative PCR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756105&req=5

Figure 4: Figure 4. Induction of aromatase expression by leptin. Aromatase mRNA expression in para-uterine fat pads from ob/ob (A) and wild-type C57BL/6 mice (B) 3 h after ip injection with saline (control), or leptin (10 μg; R&D Systems). (A and B) n = 6, mean ± SD; *P < 0.05 **P < 0.01. Gene expression was measured using real-time quantitative PCR.
Mentions: Obese women have a higher risk for hormone-dependent breast cancer development, recurrence and death38,39 and obesity has also been found to hinder breast cancer treatment.40 To address the issue of aromatase expression in obesity we compared aromatase expression in the adipose tissue of lean and obese mice in a model of diet-induced obesity (DIO). Lean six-week-old female C57BL/6J mice were placed for 16 weeks on either a high fat diet (HFD; D12492; Research Diets) in which 60% of the total calories were derived from fat or a control low fat diet (LFD; D12450B) in which 10% of the total calories were derived from fat. The HFD induced obesity whereas LFD resulted in moderate age-appropriate weight gain. After 16 weeks para-uterine adipose tissues were removed, RNA was prepared and aromatase mRNA determined by real-time PCR. Aromatase mRNA was increased more than 45 fold in adipose tissues of HFD induced obese mice compared with LFD fed lean mice (Fig. 3B). HFD-induced obesity is a model that closely resembles human obesity including a marked increase in circulating leptin. Therefore the increase in aromatase expression in HFD mice could potentially be due to higher leptin levels. To address this question further we tested aromatase expression in leptin-deficient genetically obese ob/ob mice. Aromatase mRNA in the para-uterine adipose tissue of adult obese C57BL/6J ob/ob mice was significantly lower than in matched lean wild-type control mice (Fig. 3C), suggesting that leptin drives aromatase gene expression in adipose tissue. To further test this hypothesis, we injected mice with recombinant leptin and found that leptin increased aromatase expression in the adipose tissue of leptin-deficient ob/ob mice and also in the adipose tissue of lean mice (Fig. 4). Together our results not only demonstrate that leptin signaling in the adipose tissues increases aromatase expression, but also suggest that leptin and aromatase in the local tumor microenvironment play a crucial role in development and growth of hormone-dependent breast cancer. These findings provide a foundation to understanding the regulation of aromatase in adipose tissues in general and in the tumor microenvironment specifically and can provide a rationale for targeting the adipocyte leptin-aromatase axis in the prevention and/or treatment of hormone-dependent breast cancer.

Bottom Line: Here we describe a unique animal model to study interactions between adipocytes and breast cancer cells in the tumor microenvironment.Our results suggest that local interactions between adipocytes and tumor cells are sufficient to promote the growth of hormone-dependent breast cancer.We also demonstrate that leptin signaling in adipocytes induces aromatase expression, expected to result in higher estrogen in the microenvironment thus enabling mammary tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Torrey Pines Institute for Molecular Studies; San Diego, CA USA.

ABSTRACT
The importance of the microenvironment in breast cancer growth and progression is becoming increasingly clear. Adipocytes are abundant in the mammary microenvironment, and recent studies show that adipocytes produce endocrine, inflammatory, and angiogenic factors that have tremendous potential to affect adjacent breast cancer cells. Yet, the extent to which local adipocyte function contributes to the pathogenesis of breast cancer is largely unexplored. Here we describe a unique animal model to study interactions between adipocytes and breast cancer cells in the tumor microenvironment. Our results suggest that local interactions between adipocytes and tumor cells are sufficient to promote the growth of hormone-dependent breast cancer. We also demonstrate that leptin signaling in adipocytes induces aromatase expression, expected to result in higher estrogen in the microenvironment thus enabling mammary tumorigenesis.

No MeSH data available.


Related in: MedlinePlus