SPSB1 Promotes Breast Cancer Recurrence by Potentiating c-MET Signaling

Abstract

Breast cancer mortality is principally due to tumor recurrence; however, the molecular mechanisms underlying this process are poorly understood. We now demonstrate that the suppressor of cytokine signaling protein SPSB1 is spontaneously upregulated during mammary tumor recurrence and is both necessary and sufficient to promote tumor recurrence in genetically engineered mouse models. The recurrence-promoting effects of SPSB1 result from its ability to protect cells from apoptosis induced by HER2/neu pathway inhibition or chemotherapy. This, in turn, is attributable to SPSB1 potentiation of c-MET signaling, such that preexisting SPSB1-overexpressing tumor cells are selected for following HER2/neu downregulation. Consistent with this, SPSB1 expression is positively correlated with c-MET activity in human breast cancers and with an increased risk of relapse in patients with breast cancer in a manner that is dependent upon c-MET activity. Our findings define a novel pathway that contributes to breast cancer recurrence and provide the first evidence implicating SPSB proteins in cancer. Significance The principal cause of death from breast cancer is recurrence. This study identifies SPSB1 as a critical mediator of breast cancer recurrence, suggests activation of the SPSB1/c-MET pathway as an important mechanism of therapeutic resistance in breast cancers, and emphasizes that pharmacological targets for recurrence may be unique to this stage of tumor progression.

Cotylenin A and arsenic trioxide cooperatively suppress cell proliferation and cell invasion activity in human breast cancer cells

“…Cleaved caspase-3 is used for a marker of apoptosis induction in several types of cancer cells (32). Although MCF-7 cells lack expression of caspase-3 as a result of a 47-bp deletion in exon 3 of the CASP3 gene (33), there is a report that MCF-7 cells induced apoptosis through the activation of caspase-7 instead of caspase-3 (34).…”

SPSB1 May Have MET Its Match during Breast Cancer Recurrence

“…The findings reported by Feng and colleagues (2) have the potential to enhance our understanding of mechanisms underlying breast cancer recurrence. Like most good studies, additional questions are now raised that should lead to further exploration.…”

“…Interestingly, another study had shown that human Par-4 protein harbors a recognition site for SPSB1 (10). Nevertheless, the authors could not detect interaction between murine Par-4 and SPSB1, as the homologous SPSB1 recognition site is not present in the murine Par-4 protein (2). It therefore remains to be tested whether Par-4 intersects with the SPSB1-cMET pathway during breast cancer recurrence.…”

“…In the current issue of Cancer Discovery , Feng and colleagues used such mouse models to modulate expression of HER2/neu, c-Myc, or Wnt-1 oncogenic signaling (2). By comparing paired primary and recurrent mammary tumors, they found that both mRNA and protein levels of the SP RY domain-containing S OCS B ox protein 1 (SPSB1) were significantly elevated in tumors that relapsed after oncogene withdrawal in all three transgenic mouse models.…”

Development of Serum Biomarker Panels for The Early Detection of Breast Cancer

“…It is increased in 10% of patients with stage I disease, 20% with stage II disease, 40% with stage III disease, and 75% with stage IV disease [7] . Lots of potential novel biomarkers for breast cancer detection and recurrence have been developed in the past years, such as, CA 27.29, carcinoembryonic antigen, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, urokinase plasminogen activator, plasminogen activator inhibitor 1, prostate apoptosis response 4, splA/ryanodine receptor domain and SOCS box containing 1 [8][9][10][11] , however, most of them were limited by their diagnostic value for early stage breast cancer, or lack of effective methods for large scale clinical diagnosis. Multibiomarker detection methods were also developed [12,13] , but most of them only discriminated the healthy control and breast cancer, not evaluated the diagnostic value of discriminating the benign breast diseases and breast cancer.…”