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Basal and therapy-driven hypoxia-inducible factor-1α confers resistance to endocrine therapy in estrogen receptor-positive breast.

Jia X, Hong Q, Lei L, Li D, Li J, Mo M, Wang Y, Shao Z, Shen Z, Cheng J, Liu G - Oncotarget (2015)

Bottom Line: Pre-treatment levels of HIF-1α were associated with negative clinical outcome.Furthermore, levels of HIF-1α were increased in post-treatment residual tumors compared with those in pre-treatment biopsy samples.Additionally, HIF-1α transcription was inhibited by zoledronic acid, a conventional drug for the treatment of postmenopausal osteoporosis, and was accompanied by a marked inhibition of the RAS/MAPK/ERK1/2 pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.

ABSTRACT
Resistance is an obstacle to endocrine therapy for breast cancer. We measured levels of hypoxia-inducible factor (HIF)-1α in 52 primary breast cancer patients before and after receiving neoadjuvant endocrine therapy with letrozole for at least 3 months. Pre-treatment levels of HIF-1α were associated with negative clinical outcome. Furthermore, levels of HIF-1α were increased in post-treatment residual tumors compared with those in pre-treatment biopsy samples. In animal studies, xenografts stably expressing HIF-1α were resistant to endocrine therapy with fulvestrant compared with the effects in control xenografts. Additionally, HIF-1α transcription was inhibited by zoledronic acid, a conventional drug for the treatment of postmenopausal osteoporosis, and was accompanied by a marked inhibition of the RAS/MAPK/ERK1/2 pathway. HIF-1α is a determinant of resistance to endocrine therapy and should be considered as a potential therapeutic target for overcoming endocrine resistance in estrogen receptor (ER)-positive breast cancer. In addition, zoledronic acid may overcome endocrine resistance in ER-positive human breast cancer by targeting HIF-1α transcription through inhibition of the RAS/MAPK/ERK1/2 pathway. Clinical studies on the administration of zoledronic acid as a second line treatment in patients who failed endocrine therapy should be considered to improve therapeutic outcomes in breast cancer patients.

No MeSH data available.


Related in: MedlinePlus

Stable over-expression of HIF-1α decreases the sensitivity of xenograft to fulvestrant(A) MCF-7/HIF-1α cells exhibited quicker and larger xenograft formation compared to the corresponding control groups; (B) MCF-7/HIF-1α cells exhibited larger xenograft formation compared to those formed by MCF-7/vector cells in one nude mouse; (C) The drug-sensitive MCF-7/vector xenograft tumor volumes were significantly reduced. (D) The growth of drug-resistant MCF-7/HIF-1α tumors was not affected by fulvestrant treatment.
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Figure 3: Stable over-expression of HIF-1α decreases the sensitivity of xenograft to fulvestrant(A) MCF-7/HIF-1α cells exhibited quicker and larger xenograft formation compared to the corresponding control groups; (B) MCF-7/HIF-1α cells exhibited larger xenograft formation compared to those formed by MCF-7/vector cells in one nude mouse; (C) The drug-sensitive MCF-7/vector xenograft tumor volumes were significantly reduced. (D) The growth of drug-resistant MCF-7/HIF-1α tumors was not affected by fulvestrant treatment.

Mentions: To further investigate the effect of HIF-1α on anti-estrogen treatment in vivo, MCF-7/HIF-1α and MCF-7/vector cells were used to establish a xenograft tumor model. MCF-7/HIF-1α cells exhibited quicker and larger xenograft tumor formation than those of formed by MCF-7/vector cells (Figure 3A). To further clarify the differences in the formation of tumors between MCF-7/HIF-1α and MCF-7/vector cells, we established a mouse model in which MCF-7/HIF-1α and MCF-7/vector cells were inoculated simultaneously in the right and left fat pads of the same nude mouse. The results showed that MCF-7/HIF-1α cells exhibited larger xenograft tumor formation compared with those formed by MCF-7/vector cells (Figure 3B). Following fulvestrant treatment, the volumes of the drug-sensitive MCF-7/vector xenograft tumors were significantly smaller compared to those formed in the MCF-7/HIF-1α groups (Figure 3C). In contrast, the growth of drug-resistant MCF-7/HIF-1α tumors was not affected (Figure 3D).


Basal and therapy-driven hypoxia-inducible factor-1α confers resistance to endocrine therapy in estrogen receptor-positive breast.

Jia X, Hong Q, Lei L, Li D, Li J, Mo M, Wang Y, Shao Z, Shen Z, Cheng J, Liu G - Oncotarget (2015)

Stable over-expression of HIF-1α decreases the sensitivity of xenograft to fulvestrant(A) MCF-7/HIF-1α cells exhibited quicker and larger xenograft formation compared to the corresponding control groups; (B) MCF-7/HIF-1α cells exhibited larger xenograft formation compared to those formed by MCF-7/vector cells in one nude mouse; (C) The drug-sensitive MCF-7/vector xenograft tumor volumes were significantly reduced. (D) The growth of drug-resistant MCF-7/HIF-1α tumors was not affected by fulvestrant treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496173&req=5

Figure 3: Stable over-expression of HIF-1α decreases the sensitivity of xenograft to fulvestrant(A) MCF-7/HIF-1α cells exhibited quicker and larger xenograft formation compared to the corresponding control groups; (B) MCF-7/HIF-1α cells exhibited larger xenograft formation compared to those formed by MCF-7/vector cells in one nude mouse; (C) The drug-sensitive MCF-7/vector xenograft tumor volumes were significantly reduced. (D) The growth of drug-resistant MCF-7/HIF-1α tumors was not affected by fulvestrant treatment.
Mentions: To further investigate the effect of HIF-1α on anti-estrogen treatment in vivo, MCF-7/HIF-1α and MCF-7/vector cells were used to establish a xenograft tumor model. MCF-7/HIF-1α cells exhibited quicker and larger xenograft tumor formation than those of formed by MCF-7/vector cells (Figure 3A). To further clarify the differences in the formation of tumors between MCF-7/HIF-1α and MCF-7/vector cells, we established a mouse model in which MCF-7/HIF-1α and MCF-7/vector cells were inoculated simultaneously in the right and left fat pads of the same nude mouse. The results showed that MCF-7/HIF-1α cells exhibited larger xenograft tumor formation compared with those formed by MCF-7/vector cells (Figure 3B). Following fulvestrant treatment, the volumes of the drug-sensitive MCF-7/vector xenograft tumors were significantly smaller compared to those formed in the MCF-7/HIF-1α groups (Figure 3C). In contrast, the growth of drug-resistant MCF-7/HIF-1α tumors was not affected (Figure 3D).

Bottom Line: Pre-treatment levels of HIF-1α were associated with negative clinical outcome.Furthermore, levels of HIF-1α were increased in post-treatment residual tumors compared with those in pre-treatment biopsy samples.Additionally, HIF-1α transcription was inhibited by zoledronic acid, a conventional drug for the treatment of postmenopausal osteoporosis, and was accompanied by a marked inhibition of the RAS/MAPK/ERK1/2 pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.

ABSTRACT
Resistance is an obstacle to endocrine therapy for breast cancer. We measured levels of hypoxia-inducible factor (HIF)-1α in 52 primary breast cancer patients before and after receiving neoadjuvant endocrine therapy with letrozole for at least 3 months. Pre-treatment levels of HIF-1α were associated with negative clinical outcome. Furthermore, levels of HIF-1α were increased in post-treatment residual tumors compared with those in pre-treatment biopsy samples. In animal studies, xenografts stably expressing HIF-1α were resistant to endocrine therapy with fulvestrant compared with the effects in control xenografts. Additionally, HIF-1α transcription was inhibited by zoledronic acid, a conventional drug for the treatment of postmenopausal osteoporosis, and was accompanied by a marked inhibition of the RAS/MAPK/ERK1/2 pathway. HIF-1α is a determinant of resistance to endocrine therapy and should be considered as a potential therapeutic target for overcoming endocrine resistance in estrogen receptor (ER)-positive breast cancer. In addition, zoledronic acid may overcome endocrine resistance in ER-positive human breast cancer by targeting HIF-1α transcription through inhibition of the RAS/MAPK/ERK1/2 pathway. Clinical studies on the administration of zoledronic acid as a second line treatment in patients who failed endocrine therapy should be considered to improve therapeutic outcomes in breast cancer patients.

No MeSH data available.


Related in: MedlinePlus