Metformin inhibits RANKL and sensitizes cancer stem cells to denosumab.
Elisabet CuyàsBegoña Martin-CastilloJoaquim Bosch-BarreraJavier A MenendezPublished in: Cell cycle (Georgetown, Tex.) (2017)
The increased propensity of BRCA1 mutation carriers to develop aggressive breast tumors with stem-like properties begins to be understood in terms of osteoprotegerin (OPG)-unrestricted cross-talk between RANKL-overproducing progesterone-sensor cells and cancer-initiating RANK+ responder cells that reside within pre-malignant BRCA1mut/+ breast epithelial tissue. We recently proposed that, in the absence of hormone influence, cancer-initiating cells might remain responsive to RANKL stimulation, and hence to the therapeutic effects of the anti-RANKL antibody denosumab because genomic instability induced by BRCA1 haploinsufficiency might suffice to cell-autonomously hyperactivate RANKL gene expression. Here we report that the biguanide metformin prevents BRCA1 haploinsufficiency-driven RANKL gene overexpression, thereby disrupting an auto-regulatory feedback control of RANKL-addicted cancer stem cell-like states within BRCA1mut/- cell populations. Moreover, metformin treatment elicits a synergistic decline in the breast cancer-initiating cell population and its self-renewal capacity in BRCA1-mutated basal-like breast cancer cells with bone metastasis-initiation capacity that exhibit primary resistance to denosumab in mammosphere assays. The specific targeting of RANKL/RANK signaling with denosumab is expected to revolutionize prevention and treatment strategies currently available for BRCA1 mutation carriers. Our findings provide a rationale for new denosumab/metformin combinatorial strategies to clinically manage RANKL-related breast oncogenesis and metastatic progression.
Keyphrases
- bone loss
- nuclear factor
- induced apoptosis
- bone mineral density
- cancer stem cells
- gene expression
- breast cancer risk
- cell cycle arrest
- giant cell
- single cell
- postmenopausal women
- endoplasmic reticulum stress
- cancer therapy
- squamous cell carcinoma
- cell proliferation
- breast cancer cells
- papillary thyroid
- clinical trial
- dna methylation
- copy number
- squamous cell
- drug delivery
- high throughput
- bone marrow
- mouse model
- replacement therapy
- lymph node metastasis
- estrogen receptor