Luminal breast cancer metastasis is dependent on estrogen signaling
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Luminal breast cancer is the most frequently encountered type of human breast cancer and accounts for half of all breast cancer deaths due to metastatic disease. We have developed new in vivo models of disseminated human luminal breast cancer that closely mimic the human disease. From initial lesions in the tibia, locoregional metastases develop predictably along the iliac and retroperitoneal lymph node chains. Tumors cells retain their epithelioid phenotype throughout the process of dissemination. In addition, systemically injected metastatic MCF-7 cells consistently give rise to metastases in the skeleton, floor of mouth, adrenal glands, as well as in the lungs, liver, brain and mammary fat pad. We show that growth of luminal breast cancer metastases is highly dependent on estrogen in a dose-dependent manner and that estrogen withdrawal induces rapid growth arrest of metastatic disease. On the other hand, even though micrometastases at secondary sites remain viable in the absence of estrogen, they are dormant and do not progress to macrometastases. Thus, homing to and seeding of secondary sites do not require estrogen. Moreover, in sharp contrast to basal-like breast cancer metastasis in which transforming growth factor-β signaling plays a key role, luminal breast cancer metastasis is independent of this cytokine. These findings have important implications for the development of targeted anti-metastatic therapy for luminal breast cancer.
KeywordsLuminal breast cancer Metastasis Estrogen Transforming growth factor-β
Transforming growth factor-β
Estrogen receptor α
TGF-β type II receptor gene
Estrogen receptor α gene
Progesterone receptor gene
Glyceraldehyde 3-phosphate dehydrogenase gene
Tartrate resistant acid phosphatase
Analysis of variance
Mammary fat pad
TGF-β response gene signature
This study was supported by PHS R01 CA120623 award from the National Cancer Institute, National Institutes of Health, US to M.R and by the Histology & Imaging, Bioinformatics and Preclinical Imaging Shared Resources of The Cancer Institute of New Jersey (P30 CA 72720). We wish to express our gratitude to Dr. Kenneth Nephew (Indiana University) for generously sharing his MCF-7 derived cell lines, and to Dr. Yibin Kang (Princeton University) for MDA-MB-231 and SCP2 cells.
Conflict of interest
The authors declare that they have no conflict of interest.