TGF{beta}2 in breast milk exosomes

Purpose:Pregnancy increases breast cancer risk for all women for at least 5 years after parturition. During weaning and involution the breast microenvironment becomes tumor promotional. Exosomes provide cell-cell communication during physiologic processes such as lactation, but also in breast cancer. We determined if molecules in milk exosomes from healthy lactating women modulate the development and progression of breast cancer. Experimental Design:13 nursing women provided 3 (transitional, mature, and wean) milk samples. Exosomes were extracted and MCF7 and -10A breast cells labeled. The expression of 6 proteins linked to breast cancer were measured. Based on the findings, TGFβ2 concentration in exosome samples measured, breast cells incubated with the exosomes and effect (epithelial mesenchymal transition-EMT) and EMT related proteins (E-cadherin, α-smooth muscle actin (α-SMA), filamentous (F)-actin and vimentin) measured. Results:Human milk exosomes entered benign and malignant breast cells. The greatest change in wean milk protein was in TGFβ2 (p=0.01). Exosomes with a high (but not low) level of TGFβ2 led to EMT in both cancer and benign cells, based on 1) change in cell morphology, actin cytoskeleton and loss of cell-cell junction structure and 2) increased α-SMA and vimentin and decreased E-cadherin. Conclusions:TGFβ2 is significantly upregulated in breast milk exosomes during weaning/early involution. Breast milk exosomes containing high levels of TGFβ2 induce changes in both benign and malignant breast epithelial cells consistent with the development and progression of breast cancer, suggesting a role for high TGFβ2 expressing breast milk exosomes in influencing breast cancer risk.

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