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SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling.

Publication ,  Journal Article
Feng, Y; Pan, T-C; Pant, DK; Chakrabarti, KR; Alvarez, JV; Ruth, JR; Chodosh, LA
Published in: Cancer Discov
July 2014

UNLABELLED: 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 pharmacologic targets for recurrence may be unique to this stage of tumor progression.

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Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

July 2014

Volume

4

Issue

7

Start / End Page

790 / 803

Location

United States

Related Subject Headings

  • Suppressor of Cytokine Signaling Proteins
  • Signal Transduction
  • Proto-Oncogene Proteins c-met
  • Oligonucleotide Array Sequence Analysis
  • Neoplasm Recurrence, Local
  • Mice
  • Mammary Neoplasms, Experimental
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Female
 

Citation

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Feng, Y., Pan, T.-C., Pant, D. K., Chakrabarti, K. R., Alvarez, J. V., Ruth, J. R., & Chodosh, L. A. (2014). SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling. Cancer Discov, 4(7), 790–803. https://doi.org/10.1158/2159-8290.CD-13-0548
Feng, Yi, Tien-Chi Pan, Dhruv K. Pant, Kristi R. Chakrabarti, James V. Alvarez, Jason R. Ruth, and Lewis A. Chodosh. “SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling.Cancer Discov 4, no. 7 (July 2014): 790–803. https://doi.org/10.1158/2159-8290.CD-13-0548.
Feng Y, Pan T-C, Pant DK, Chakrabarti KR, Alvarez JV, Ruth JR, et al. SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling. Cancer Discov. 2014 Jul;4(7):790–803.
Feng, Yi, et al. “SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling.Cancer Discov, vol. 4, no. 7, July 2014, pp. 790–803. Pubmed, doi:10.1158/2159-8290.CD-13-0548.
Feng Y, Pan T-C, Pant DK, Chakrabarti KR, Alvarez JV, Ruth JR, Chodosh LA. SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling. Cancer Discov. 2014 Jul;4(7):790–803.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

July 2014

Volume

4

Issue

7

Start / End Page

790 / 803

Location

United States

Related Subject Headings

  • Suppressor of Cytokine Signaling Proteins
  • Signal Transduction
  • Proto-Oncogene Proteins c-met
  • Oligonucleotide Array Sequence Analysis
  • Neoplasm Recurrence, Local
  • Mice
  • Mammary Neoplasms, Experimental
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Female