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ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Cancer Endocrinology
Volume 15 - 2024 | doi: 10.3389/fendo.2024.1450648

Insulin-Like Growth Factor Binding Protein-6 Modulates Proliferative Antagonism in Response to Progesterone in Breast Cancer

Provisionally accepted
Francisco J Lariz Francisco J Lariz Pacha B Botero Pacha B Botero Isabella Shoffstall Isabella Shoffstall Kevin D Houston Kevin D Houston *
  • New Mexico State University, Las Cruces, United States

The final, formatted version of the article will be published soon.

    Breast cancer is one of the most diagnosed cancers worldwide. The insulin-like growth factor (IGF) system promotes proliferation and survival in breast cancer cells and is regulated by 6 insulin-like growth factor binding proteins (IGFBPs). The IGFBPs sequester IGFs to prolong their half-life and attenuate binding to insulin-like growth factor 1 receptor (IGF1R). While IGFBP-6 has been studied in some cancers it has not been studied extensively in hormone receptor positive breast cancer. Survival analysis using available databases indicated that high IGFBP-6 levels improve overall survival in progesterone receptor positive breast cancers. IGFBP-6 is transcriptionally induced by progesterone in T47D breast cancer cells resulting in increased intracellular and extracellular IGFBP-6 protein. Knockdown of IGFBP-6 resulted in reduced proliferative antagonism when estradiol stimulated T47D cells were cotreated with progesterone and protein levels of both progesterone receptor isoforms (PR-A and PR-B) were decreased following knockdown of IGFBP-6. P21(Cip1/Waf1), which is progesterone responsive, was not induced in response to progesterone following knockdown of IGFBP-6. Cyclin E2, a cell cycle regulator, is induced by progesterone only when IGFBP-6 is knocked down. Stable overexpression of IGFBP-6 in MCF-7 cells resulted in an increase in Epidermal Growth Factor Receptor (EGFR) and this expression was further enhanced when cells were cotreated with progesterone and estradiol. These results indicate that IGFBP-6 is a regulator of progesterone action, and that PR is required for the observed protective effects of IGFBP-6 in breast cancer.

    Keywords: breast cancer, Progesterone, Progesterone Receptor, Insulin-like growth factor binding protein, steroid hormones

    Received: 17 Jun 2024; Accepted: 04 Nov 2024.

    Copyright: © 2024 Lariz, Botero, Shoffstall and Houston. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Kevin D Houston, New Mexico State University, Las Cruces, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.