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The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.

Publication ,  Journal Article
Cocce, KJ; Jasper, JS; Desautels, TK; Everett, L; Wardell, S; Westerling, T; Baldi, R; Wright, TM; Tavares, K; Yllanes, A; Bae, Y; Blitzer, JT ...
Published in: Cell Rep
October 22, 2019

Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly inevitable, we undertook a study to identify and exploit targetable vulnerabilities that were manifest in endocrine therapy-resistant disease. Using cellular and mouse models of endocrine therapy-sensitive and endocrine therapy-resistant breast cancer, together with contemporary discovery platforms, we identified a targetable pathway that is composed of the transcription factors FOXA1 and GRHL2, a coregulated target gene, the membrane receptor LYPD3, and the LYPD3 ligand, AGR2. Inhibition of the activity of this pathway using blocking antibodies directed against LYPD3 or AGR2 inhibits the growth of endocrine therapy-resistant tumors in mice, providing the rationale for near-term clinical development of humanized antibodies directed against these proteins.

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Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

October 22, 2019

Volume

29

Issue

4

Start / End Page

889 / 903.e10

Location

United States

Related Subject Headings

  • Transcription Factors
  • Oncogene Proteins
  • Mucoproteins
  • Mice
  • Mammary Neoplasms, Experimental
  • MCF-7 Cells
  • Humans
  • Hepatocyte Nuclear Factor 3-alpha
  • GPI-Linked Proteins
  • Female
 

Citation

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Cocce, K. J., Jasper, J. S., Desautels, T. K., Everett, L., Wardell, S., Westerling, T., … McDonnell, D. P. (2019). The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer. Cell Rep, 29(4), 889-903.e10. https://doi.org/10.1016/j.celrep.2019.09.032
Cocce, Kimberly J., Jeff S. Jasper, Taylor K. Desautels, Logan Everett, Suzanne Wardell, Thomas Westerling, Robert Baldi, et al. “The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.Cell Rep 29, no. 4 (October 22, 2019): 889-903.e10. https://doi.org/10.1016/j.celrep.2019.09.032.
Cocce KJ, Jasper JS, Desautels TK, Everett L, Wardell S, Westerling T, et al. The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer. Cell Rep. 2019 Oct 22;29(4):889-903.e10.
Cocce, Kimberly J., et al. “The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.Cell Rep, vol. 29, no. 4, Oct. 2019, pp. 889-903.e10. Pubmed, doi:10.1016/j.celrep.2019.09.032.
Cocce KJ, Jasper JS, Desautels TK, Everett L, Wardell S, Westerling T, Baldi R, Wright TM, Tavares K, Yllanes A, Bae Y, Blitzer JT, Logsdon C, Rakiec DP, Ruddy DA, Jiang T, Broadwater G, Hyslop T, Hall A, Laine M, Phung L, Greene GL, Martin L-A, Pancholi S, Dowsett M, Detre S, Marks JR, Crawford GE, Brown M, Norris JD, Chang C-Y, McDonnell DP. The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer. Cell Rep. 2019 Oct 22;29(4):889-903.e10.
Journal cover image

Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

October 22, 2019

Volume

29

Issue

4

Start / End Page

889 / 903.e10

Location

United States

Related Subject Headings

  • Transcription Factors
  • Oncogene Proteins
  • Mucoproteins
  • Mice
  • Mammary Neoplasms, Experimental
  • MCF-7 Cells
  • Humans
  • Hepatocyte Nuclear Factor 3-alpha
  • GPI-Linked Proteins
  • Female