Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo

Laura Wright, Ahmed A. Harhash, Wende M. Kozlow, David L. Waning, Jenna Regan, Yun She, Sutha K. John, Sreemala Murthy, Maryla Niewolna, Andrew R. Marks, Khalid Mohammad, Theresa Guise

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Aromatase inhibitors (AIs) cause muscle weakness, bone loss, and joint pain in up to half of cancer patients. Preclinical studies have demonstrated that increased osteoclastic bone resorption can impair muscle contractility and prime the bone microenvironment to accelerate metastatic growth. We hypothesized that AIinduced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases. Female athymic nude mice underwent ovariectomy (OVX) or sham surgery and were treated with vehicle or AI (letrozole; Let). An OVX-Let group was then further treated with bisphosphonate (zoledronic acid; Zol). At week three, trabecular bone volume was measured and mice were inoculated with MDA-MB-231 cells into the cardiac ventricle and followed for progression of bone metastases. Five weeks after tumor cell inoculation, tumorinduced osteolytic lesion area was increased in OVX-Let mice and reduced in OVX-Let- Zol mice compared to sham-vehicle. Tumor burden in bone was increased in OVX-Let mice relative to sham-vehicle and OVX-Let-Zol mice. At the termination of the study, muscle-specific force of the extensor digitorum longus muscle was reduced in OVXLet mice compared to sham-vehicle mice, however, the addition of Zol improved muscle function. In summary, AI treatment induced bone loss and skeletal muscle weakness, recapitulating effects observed in cancer patients. Prevention of AI-induced osteoclastic bone resorption using a bisphosphonate attenuated the development of breast cancer bone metastases and improved muscle function in mice. These findings highlight the bone microenvironment as a modulator of tumor growth locally and muscle function systemically.

Original languageEnglish (US)
Pages (from-to)8406-8419
Number of pages14
JournalOncotarget
Volume8
Issue number5
DOIs
StatePublished - 2017

Fingerprint

Bone Neoplasms
Aromatase Inhibitors
Muscle Weakness
Estrogen Receptors
Breast Neoplasms
Bone and Bones
Muscles
zoledronic acid
letrozole
Diphosphonates
Bone Resorption
Neoplasm Metastasis
Nude Mice
Neoplasms
Arthralgia
Ovariectomy
Growth
Tumor Burden
Heart Ventricles
Skeletal Muscle

Keywords

  • Aromatase inhibitor
  • Bone
  • Breast cancer
  • Metastasis
  • Skeletal muscle

ASJC Scopus subject areas

  • Oncology

Cite this

Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo. / Wright, Laura; Harhash, Ahmed A.; Kozlow, Wende M.; Waning, David L.; Regan, Jenna; She, Yun; John, Sutha K.; Murthy, Sreemala; Niewolna, Maryla; Marks, Andrew R.; Mohammad, Khalid; Guise, Theresa.

In: Oncotarget, Vol. 8, No. 5, 2017, p. 8406-8419.

Research output: Contribution to journalArticle

Wright, Laura ; Harhash, Ahmed A. ; Kozlow, Wende M. ; Waning, David L. ; Regan, Jenna ; She, Yun ; John, Sutha K. ; Murthy, Sreemala ; Niewolna, Maryla ; Marks, Andrew R. ; Mohammad, Khalid ; Guise, Theresa. / Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo. In: Oncotarget. 2017 ; Vol. 8, No. 5. pp. 8406-8419.
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AU - Harhash, Ahmed A.

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AU - Waning, David L.

AU - Regan, Jenna

AU - She, Yun

AU - John, Sutha K.

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AU - Marks, Andrew R.

AU - Mohammad, Khalid

AU - Guise, Theresa

PY - 2017

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AB - Aromatase inhibitors (AIs) cause muscle weakness, bone loss, and joint pain in up to half of cancer patients. Preclinical studies have demonstrated that increased osteoclastic bone resorption can impair muscle contractility and prime the bone microenvironment to accelerate metastatic growth. We hypothesized that AIinduced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases. Female athymic nude mice underwent ovariectomy (OVX) or sham surgery and were treated with vehicle or AI (letrozole; Let). An OVX-Let group was then further treated with bisphosphonate (zoledronic acid; Zol). At week three, trabecular bone volume was measured and mice were inoculated with MDA-MB-231 cells into the cardiac ventricle and followed for progression of bone metastases. Five weeks after tumor cell inoculation, tumorinduced osteolytic lesion area was increased in OVX-Let mice and reduced in OVX-Let- Zol mice compared to sham-vehicle. Tumor burden in bone was increased in OVX-Let mice relative to sham-vehicle and OVX-Let-Zol mice. At the termination of the study, muscle-specific force of the extensor digitorum longus muscle was reduced in OVXLet mice compared to sham-vehicle mice, however, the addition of Zol improved muscle function. In summary, AI treatment induced bone loss and skeletal muscle weakness, recapitulating effects observed in cancer patients. Prevention of AI-induced osteoclastic bone resorption using a bisphosphonate attenuated the development of breast cancer bone metastases and improved muscle function in mice. These findings highlight the bone microenvironment as a modulator of tumor growth locally and muscle function systemically.

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