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Adiponectin is the major adipocytes‐secreted protein involved in obesity‐related breast cancer growth and progression. We proved that adiponectin promotes proliferation in ERα‐positive breast cancer cells, through ERα transactivation and the recruitment of LKB1 as ERα‐coactivator. Here, we showed that adiponectin‐mediated ERα transactivation enhances E‐cadherin expression. Thus, we investigated the molecular mechanism through which ERα/LKB1 complex may modulate the expression of E‐cadherin, influencing tumor growth, progression and distant metastasis. We demonstrated that adiponectin increases E‐cadherin expression in ERα‐positive 2D and higher extent in 3D cultures. This occurs through a direct activation of E‐cadherin gene promoter by ERα/LKB1‐complex. The impact of E‐cadherin on ERα‐positive breast cancer cell proliferation comes from the evidence that in the presence of E‐cadherin siRNA the proliferative effects of adiponectin is no longer noticeable. Since E‐cadherin connects cell polarity and growth, we investigated if the adiponectin‐enhanced E‐cadherin expression could influence the localization of proteins cooperating in cell polarity, such as LKB1 and Cdc42. Surprisingly, immunofluorescence showed that, in adiponectin‐treated MCF‐7 cells, LKB1 and Cdc42 mostly colocalize in the nucleus, impairing their cytosolic cooperation in maintaining cell polarity. The orthotopic implantation of MCF‐7 cells revealed an enhanced E‐cadherin‐mediated breast cancer growth induced by adiponectin. Moreover, tail vein injection of MCF‐7 cells showed a higher metastatic burden in the lungs of mice receiving adiponectin‐treated cells compared to control. From these findings it emerges that adiponectin treatment enhances E‐cadherin expression, alters cell polarity and stimulates ERα‐positive breast cancer cell growth in vitro and in vivo, sustaining higher distant metastatic burden. [ABSTRACT FROM AUTHOR]

Adipose tissue is a metabolic and endocrine organ that secretes bioactive molecules called adipocytokines. Among these, adiponectin has a crucial role in obesity-associated breast cancer. The key molecule of adiponectin signaling is AMPK, which is mainly activated by liver kinase B1 (LKB1). Here, we demonstrated that estrogen receptor-a (ERa)/LKB1 interaction may negatively interfere with the LKB1 capability to phosphorylate AMPK and inhibit its downstream signaling TSC2/mTOR/p70S6k. In adiponectin-treated MCF-7 cells, AMPK signaling was not working, resulting in its downstream target acetyl-CoA carboxylase (ACC) being still active. In contrast, in MDA-MB-231 cells, AMPK and ACC phosphorylation was enhanced by adiponectin, inhibiting lipogenesis and cell growth. Upon adiponectin, ERa signaling switched the energy balance of breast cancer cells toward a lipogenic phenotype. Therefore, adiponectin played an inhibitory role on ERa-negative cell growth and progression in vitro and in vivo. In contrast, low adiponectin levels, similar to those circulating in obese patients, acted on ERa-positive cells as a growth factor, stimulating proliferation. The latter effect was blunted in vivo by high adiponectin concentration. All this may have translational relevance, addressing how the handling of adiponectin, as a therapeutic tool in breast cancer treatment, needs to be carefully considered in ERa-positive obese patients, where circulating levels of this adipocytokine are relatively low. In other words, in ERa-positive breast cancer obese patients, higher adiponectin doses should be administered with respect to ERa-negative breast cancer, also opportunely combined with antiestrogen therapy. [ABSTRACT FROM AUTHOR]

Exosomes—small membrane vesicles secreted by both normal and malignant cells upon fusion of endosomal multivesicular bodies (MVBs) with the plasma membrane—play an important role in cell-to-cell communication. During the last decade, several reports have highlighted the involvement of these nanovesicles in many aspects of breast cancer development and progression, but the extracellular signals governing their generation in breast cancer cells have not been completely unraveled. Here, we investigated the role of the obesity hormone leptin, a well-known adipokine implicated in mammary tumorigenesis, on the mechanisms regulating exosome biogenesis and release in both estrogen receptor α (ERα)—positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells. We found that leptin treatment enhanced the number of MVBs in the cytoplasm of breast cancer cells and increased the amount of exosomes released in cell conditioned media. At molecular level, leptin increased the protein expression of Tsg101—a key component of the endosomal sorting complex required for transport I (ESCRT-I)—by a post-transcriptional mechanism involving its direct interaction with the chaperone protein Hsp90. Targeting leptin signaling, by a selective leptin receptor antagonist the peptide LDFI (Leu-Asp-Phe-Ile), abrogated leptin effects on Tsg101 expression and on exosome secretion in breast cancer cells. In conclusion, our findings, identifying for the first time leptin/leptin receptor/Hsp90 axis as an important regulator of exosome generation in mammary carcinoma cells, suggest that targeting this signaling pathway might represent a novel therapeutic strategy to impair exosome secretion and interrupt the dangerous cell-to-cell communication in breast cancer. [ABSTRACT FROM AUTHOR]