Abstract
Among the molecular subtypes of breast cancer are luminal (A or B) estrogen receptor positive (ER+), HER2+, and triple negative (basal-like). In addition to the molecular subtypes, there are 18 histologic breast cancer subtypes classified on appearance, including invasive lobular breast carcinoma (ILC), which are 8–15% of all breast cancers and are largely ER+ tumors. We used a new model of ER+ ILC, called BCK4. To determine the estrogen regulated genes in our ILC model, we examined BCK4 xenograft tumors from mice supplemented with or without estrogen using gene expression arrays. Approximately 3000 genes were regulated by estrogen in vivo. Hierarchical cluster analyses of the BCK4 derived tumors compared with ER+ and ER- breast cancer cell lines show the estrogen treated BCK4 tumors group with ER- breast cancers most likely due to a high proliferation score, while tumors from cellulose supplemented mice were more related to ER+ breast tumor cells. To elucidate genes regulated in vitro by estrogen in BCK4 cells, we performed expression profiling using Illumina arrays of the BCK4 cell line, treated with or without estrogen in vitro. A set of ~200 overlapping genes were regulated by estrogen in the BCK4 cell line and xenograft tumors, and pathway analysis revealed that the c-Kit pathway might be a target to reduce estrogen-induced proliferation. Subsequent studies found that inhibition of c-Kit activity using imatinib mesylate (Gleevec®) blocked estrogen mediated stimulation of BCK4 tumors and BCK4 cells in vitro as effectively as the anti-estrogen fulvestrant (Faslodex®). Decreased expression of c-Kit using shRNA also decreased baseline and estrogen induced proliferation in vitro and in vivo. These studies are the first to indicate that c-Kit inhibition is an effective approach to target c-Kit+ ILC.
Highlights
There are at least 18 different histological subtypes of breast cancer
Intrinsic subtype analysis of BCK4 cells BCK4 cells have been in culture a relatively short time compared with other widely used breast cancer cell lines, the majority of which were established in the 1970s
We examined the effects of imatinib on two other ER+ invasive lobular carcinoma (ILC) cell lines, SUM44 and MM134, where it decrease in baseline and E2 induced proliferation respectively vs. the shNT control (Fig. 5c)
Summary
There are at least 18 different histological subtypes of breast cancer. Among these are invasive breast carcinoma of no special type (IC-NST, formerly known as invasive ductal carcinoma), invasive lobular carcinoma (ILC) which comprise 8–15% of all breast tumors, and mucinsecreting mucinous breast cancers (MBC; >90% mucin) that comprise ~4% of all breast cancers. Most MBC are considered ductal in origin because of their secretion of extracellular mucin, there are several recent reports of ILC that produce extracellular mucus[1,2,3], and expression profiling of 11 histological subtypes shows some mucinous tumors are similar to ILC4, suggesting these breast cancer subtypes may be related. The presence of signet ring (SR) cells (so named because of displacement of the nucleus from the intracytoplasmic containment of mucin) may or may not be noted by pathologists if the cells account for less than
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