StarD13 is a tumor suppressor in breast cancer that regulates cell motility and invasion

Abstract

Breast cancer is one of the most commonly diagnosed cancers in women around the world. In general, the more aggressive the tumor, the more rapidly it grows and the more likely it metastasizes. Members of the Rho subfamily of small GTP-binding proteins (GTPases) play a central role in breast cancer cell motility and metastasis. The switch between active GTP-bound and inactive GDP-bound state is regulated by guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and guanine-nucleotide dissociation inhibitors (GDIs). We studied the role of StarD13, a recently identified Rho-GAP that specifically inhibits the function of RhoA and Cdc42. We aimed to investigate its role in breast cancer proliferation and metastasis. The levels of expression of this Rho-GAP in tumor tissues of different grades were assayed using immunohistochemistry. We observed that, while the level of StarD13 expression decreases in cancer tissues compared to normal tissues, it increases as the grade of the tumor increased. This was consistent with the fact that although StarD13 was indeed a tumor suppressor in our breast cancer cells, as seen by its effect on cell proliferation, it was needed for cancer cell motility. In fact, StarD13 knockdown resulted in an inhibition of cell motility and cells were not able to detach their tail and move forward. Our study describes, for the first time, a tumor suppressor that plays a positive role in cancer motility.

In vivo evidence supporting a metastasis suppressor role for Stard13 (Dlc2) in ErbB2 (Neu) oncogene induced mouse mammary tumors

“…Also, these high risk patients showed reduced metastasis and recurrence free survival with no difference in overall survival when compared with to the low risk patient None of the groups showed any significant change as determined by Mann-Whitney U Test. 6 In contrast, another study showed that knockdown of DLC2 in the HepG2 hepatocellular carcinoma line showed increase cell motility in transwell migration assays. The graph is represented in scatter dot plot with mean 6 SEM.…”

“…5 Another study showed that STARD13 was expressed at lower levels in stage I & II breast cancers compared to stage 0, however, its expression was elevated in higher grade tumors. 6 Knockdown of STARD13 resulted in less motility in 2D cultures, but increased invasiveness in 3D cultures. 6 The 3 0 UTR of STARD13 mRNA is targeted by the miR-125b microRNA and expression of a miR-125b mimic in the MCF7 cell line resulted in increased metastases in tumor xenografts.…”

“…6 Knockdown of STARD13 resulted in less motility in 2D cultures, but increased invasiveness in 3D cultures. 6 The 3 0 UTR of STARD13 mRNA is targeted by the miR-125b microRNA and expression of a miR-125b mimic in the MCF7 cell line resulted in increased metastases in tumor xenografts. 7 STARD13 was among 490 genes that showed significant methylation and low expression among the hypermethylated group of breast cancers.…”

“…One report showed that overexpression of STARD13 inhibits MCF7 breast cancer cell line growth. 6 Knockdown of STARD13 resulted in less motility in 2D cultures, but increased invasiveness in 3D cultures. 5 Another study showed that STARD13 was expressed at lower levels in stage I & II breast cancers compared to stage 0, however, its expression was elevated in higher grade tumors.…”

“…5 The MCF7 and MDA-MB-231 cell lines showed expression of a truncated STARD13 transcript. 6 The 3 0 UTR of STARD13 mRNA is targeted by the miR-125b microRNA and expression of a miR-125b mimic in the MCF7 cell line resulted in increased metastases in tumor xenografts. 6 Knockdown of STARD13 resulted in less motility in 2D cultures, but increased invasiveness in 3D cultures.…”