**2.4 Breast**

EV studies relating to both breast and prostate cancer highlight many of the salient principles observed in lung cancer studies, and also exhibit the promising roles that EV play in evolving chemoresistance. As we will come to see across a variety of cancer models and disease states, EV function carries great pluralityexhibiting multiple, and often times contradictory effects depending on their cellular origin and physiological state [48].

In breast cancer, while healthy mammary epithelial cells within the breast stroma secrete EVs that prevent the release of breast cancer derived EVs, the EVs shed by the disease cells promote the opposite, imparting an immense impact on chemoresistance. Cancer derived EVs are known to shuttle pro-oncogenic proteins and nucleic acids from diseases cells to surrounding healthy stroma and connective tissue [61]. Zhou et al. reported that breast cancer secreted exosomes are enriched in particular RNA species, such as miR-105, which destroys the vascular endothelial barrier, allowing cancer to enter the circulation and spread [62]. Studies employing fluorescently labeled miRNA-loaded EVs showed that tamoxifen resistant breast cancer cells *in vitro* can carry multiple miRNA profiles. EVs packed with fluorescently-tagged miR-221/222 can also shuttle their cargo to sensitive cells of the same type, thereby transferring resistance RNAs which effectively reduced gene expression of P27 and estrogen receptor-α (ERα) in target cell. The loss of p27 has been linked to drug resistance, as it is able to take a cell that is arrested in its cell cycle and stimulate its reentry back into active cycling [63]. However, as discussed, healthy stromal cells counteract the effects of oncogenic vesicles. This competition between "good" and "bad" vesicles is a fine balance; a yin/yang that loses equilibrium as cancer overwhelms healthy stoma. When stromal cells are outcompeted and significantly influenced by oncogenic EV signaling, the now altered stroma in turn activates STAT1 and NOTCH3 signaling in breast cancer cells, promoting cancer initiating cell populations responsible for drug resistance and nascent tumor formation [64]. This is a common theme in EV-mediated cancer progression which we will see is universal across numerous solid and hematological cancers.
