Loss of Tumor Suppressor Gene Promotes Breast Cancer Metastasis into the Lungs

Cancer researchers have found that loss of a specific tumor suppressor gene promotes the metastasis of breast cancer cells into the lungs.

Investigators at the Institute for Research in Biomedicine (Barcelona, Spain) characterized the biological activity of RARRES3 (retinoic acid receptor responder protein 3), a recently identified metastasis suppressor gene whose reduced expression in primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. This work was carried out on samples from mice and in cell lines, and then was validated in 580 samples from human primary breast cancer tumors.

Results published in the May 27, 2014, online edition of the journal EMBO Molecular Medicine revealed that the loss of function of the RARRES3 gene in primary breast tumor cells promoted metastasis to the lung. RARRES3 downregulation engaged metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributed to lung metastasis.

Looking at the results from the other direction, it was clear that the investigators had shown that RARRES3 blocked adhesion to the lung parenchyma and, second, the phospholipase activity of RARRES3 stimulated differentiation attributes, thus blunting metastasis-initiating functions at the lung required for the breast cancer cells to establish a lesion.

"RARRES3 is suppressed in estrogen receptor-negative (ER-) breast cancer tumors, thus stimulating the later invasion of the cancer cells and conferring them a greater malignant capacity," said senior author Dr. Roger Gomis, head of the growth control and cancer metastasis laboratory at the Institute for Research in Biomedicine. "The transformation of a normal cell into an invasive tumor cell is not just about acquiring capacities but equally important is the loss of certain genes, such as RARRES3."

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