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The tumor microenvironment (TME) is a complex infrastructure composed of stromal, epithelial, and immune cells embedded in a vasculature ECM. The microenvironment surrounding mammary epithelium plays a critical role during the development and differentiation of the mammary gland, enabling the coordination of the complex multihormones and growth factor signaling processes. Progesterone/progesterone receptor paracrine signaling interactions in the microenvironment play vital roles in stem/progenitor cell function during normal breast development. In breast cancer, the female sex hormones, estrogen and progesterone, and growth factor signals are altered in the TME. Progesterone signaling modulates not only breast tumors but also the breast TME, leading to the activation of a series of cross-communications that are implicated in the genesis of breast cancers. This chapter reviews the evidence that progesterone and PR signaling modulates not only breast epitheliums but also the breast TME. Furthermore, crosstalk between estrogen and progesterone signaling affecting different cell types within the TME is discussed. A better understanding of how PR and progesterone affect the TME of breast cancer may lead to novel drugs or a therapeutic approach for the treatment of breast cancer shortly.

Triple-negative breast cancer (TNBC) affects only about 10-15% of women with breast cancer (BC) but accounts for almost 50% of all BC deaths. At this time, development of targeted treatments for TNBC are urgently needed. Insulin-like growth factor-2 (IGF2) is highly expressed in TNBCs and mediates its proliferative effects via two hormone receptors, insulin-like growth factor -1 receptor (IGF1R) and insulin receptor (IR). Using a TNBC tissue microarray (TMA) consisting of 159 archival clinical samples, we confirm that IGF2 is highly expressed in tumor tissue as compared to nearby normal tissue (P Citation Format: Nalo M. Hamilton, Diana Marquez-Garban, David Austin, Neda Moatamed, Lorena P. Burton, David Elashoff, Begonya Comin-Anduix, Tristan Grogan, Madhuri Wadehra, Helena Chang, Adrienne Martinez, Mary-Lynn Brecht, Isabel Jabara, Richard Pietras, Yahya Elshimali, Jaydutt Vadgama, Michael Jung. Insulin-like growth factor-2 a potential target for screening and treatment in patients with triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 943.

Triple-negative breast cancer (TNBC) affects only about 10-15% of women with breast cancer (BC) but accounts for almost 50% of all BC deaths. At this time, development of targeted treatments for TNBC is urgently needed. Insulin-like growth factor-2 (IGF2) is highly expressed in TNBCs in African-American and Latina patients. Since hormone receptors, like insulin-like growth factor-1/insulin (IGF1R/IR, are known to be enriched and to cross-communicate in subtypes of TNBC, we assessed effects of IGF1R/IR antagonists on proliferation of human and murine TNBC cells in vitro. Combination treatment of BMS-754807 (IGF1R/IR) with NVP-AEW541 (IGF1R inhibitor) reduced proliferation of human MDA-MB-231, BT549, HCC1937 and murine 4T1 TNBC cells in vitro (P Citation Format: Nalo M. Hamilton, Diana C. Marquez-Garban, Lorena P. Burton, Begonya Comin-Anduix, Alejandro J. Garcia, Jaydutt V. Vadgama. Combination of insulin-like growth factor-1 receptor/insulin receptor (IGF1R/IR) antagonist with anti-PD-L1 antibody blocks triple-negative breast cancer (TNBC) progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-391.