In vivo detection of HSP90 identifies breast cancers with aggressive behavior

Purpose: Heat shock protein 90 (Hsp90), a chaperone to numerous molecular pathways in malignant cells, is elevated in aggressive breast cancers (BC). We hypothesized that identifying breast cells with elevated Hsp90 activity in situ could result in early detection of aggressive BC. Experimental Design: We exploited the uptake of a Hsp90 inhibitor by malignant cells to create an imaging probe (HS131) of Hsp90 activity by linking it to a near infrared (nIR) dye. HS131 uptake into cells correlated with cell membrane expression of Hsp90 and was used to image molecular subtypes of murine and human BC in vitro and in murine models. Results: HS131 imaging was both sensitive and specific in detecting the murine 4T1 BC cell line, as well as subclones with differing metastatic potential. Highly metastatic subclones (4T07) had high HS131 uptake, but subclones with lower metastatic potential (67NR, 168FARN) had low HS131 uptake. We generated isogenic cell lines to demonstrate that overexpression of a variety of specific oncogenes resulted in high HS131 uptake and retention. Finally, we demonstrated that HS131 could be used to detect spontaneous tumors in MMTV-neu mice, as well as primary and metastatic human BC xenografts. HS131 could image invasive lobular BC, a histologic subtype of BC which is often undetectable by mammography. Conclusions: An HSP90-targeting nIR probe is sensitive and specific in imaging all molecular subtypes of murine and human BC, with higher uptake in aggressive and highly metastatic clones. Clinical studies with Hsp90-targeting nIR probes will be initiated shortly.

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