Androgens enhance the ability of intratumoral macrophages to promote breast cancer progression

Yamaguchi,Mio; Takagi,Kiyoshi; Sato,Masayasu; Sato,Ai; Miki,Yasuhiro; Onodera,Yoshiaki; Miyashita,Minoru; Sasano,Hironobu; Suzuki,Takashi

doi:10.3892/or.2021.8139

Androgens enhance the ability of intratumoral macrophages to promote breast cancer progression

Authors:
- Mio Yamaguchi
- Kiyoshi Takagi
- Masayasu Sato
- Ai Sato
- Yasuhiro Miki
- Yoshiaki Onodera
- Minoru Miyashita
- Hironobu Sasano
- Takashi Suzuki
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Affiliations: Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Miyagi‑ken 980‑8575, Japan, Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science, Tohoku University, Sendai, Miyagi 980‑8574, Japan, Department of Anatomic Pathology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980‑8575, Japan, Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980‑8575, Japan
Published online on: July 12, 2021 https://doi.org/10.3892/or.2021.8139
Article Number: 188

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Abstract

Androgens are produced locally in breast carcinoma tissues by androgen‑producing enzymes such as 5α‑reductase type 1 (5αRed1) and affect not only breast cancer cells but the tumor microenvironment as well. Tumor‑associated macrophages (TAMs) are primary components of the tumor microenvironment and contribute to tumor progression. Although previous studies suggest that androgen/androgen receptor (AR) signaling in macrophages has important roles in human diseases, androgen action on TAMs has remained largely unknown. We immunolocalized macrophage marker CD163 as well as AR and 5αRed1 in 116 breast carcinomas and correlated them with clinicopathological parameters and clinical outcomes. Moreover, we examined the roles of androgens on macrophages in breast cancer progression using cell lines 4T1 (mouse breast cancer) and RAW264.7 (macrophage) in a tumor‑bearing female BALB/c mouse model. Double immunohistochemistry revealed that AR was sporadically expressed in the macrophages in breast carcinoma tissues. Macrophage infiltration was significantly correlated with an aggressive phenotype of breast carcinomas and worse prognosis, especially in the 5αRed1‑positive group. In a sphere‑forming assay using 4T1 and RAW‑AR cells, which stably express AR, the sphere size was significantly increased due to androgens when 4T1 cells were cocultured with RAW‑AR cells. Furthermore, in vivo experiments revealed that tumor growth and Ki67, a cell proliferation marker, were increased when androgens were stably produced in breast cancer cells and AR was expressed in macrophages. In conclusion, AR is expressed in intratumoral macrophages and is associated with an aggressive phenotype of breast carcinomas, especially when breast cancer cells actively produce androgens. Thus, androgens may enhance the ability of macrophages to promote breast cancer progression.

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1	Luqmani YA and Alam-Eldin N: Overcoming resistance to endocrine therapy in breast cancer: New approaches to a nagging problem. Med Princ Pract. 25 (Suppl 2):S28–S40. 2016. View Article : Google Scholar
2	Suzuki T, Darnel AD, Akahira JI, Ariga N, Ogawa S, Kaneko C, Takeyama J, Moriya T and Sasano H: 5alpha-reductases in human breast carcinoma: Possible modulator of in situ androgenic actions. J Clin Endocrinol Metab. 86:2250–2257. 2001. View Article : Google Scholar : PubMed/NCBI
3	Suzuki T, Miki Y, Moriya T, Akahira J, Ishida T, Hirakawa H, Yamaguchi Y, Hayashi S and Sasano H: 5Alpha-reductase type 1 and aromatase in breast carcinoma as regulators of in situ androgen production. Int J Cancer. 120:285–291. 2007. View Article : Google Scholar : PubMed/NCBI
4	Hall RE, Aspinall JO, Horsfall DJ, Birrell SN, Bentel JM, Sutherland RL and Tilley WD: Expression of the androgen receptor and an androgen-responsive protein, apolipoprotein D, in human breast cancer. Br J Cancer. 74:1175–1180. 1996. View Article : Google Scholar : PubMed/NCBI
5	Kuenen-Boumeester V, Van der Kwast TH, Claassen CC, Look MP, Liem GS, Klijn JG and Henzen-Logmans SC: The clinical significance of androgen receptors in breast cancer and their relation to histological and cell biological parameters. Eur J Cancer. 32A:1560–1565. 1996. View Article : Google Scholar : PubMed/NCBI
6	Vera-Badillo FE, Templeton AJ, de Gouveia P, Diaz-Padilla I, Bedard PL, Al-Mubarak M, Seruga B, Tannock IF, Ocana A and Amir E: Androgen receptor expression and outcomes in early breast cancer: A systematic review and meta-analysis. J Natl Cancer Inst. 106:djt3192014. View Article : Google Scholar : PubMed/NCBI
7	Farmer P, Bonnefoi H, Becette V, Tubiana-Hulin M, Fumoleau P, Larsimont D, Macgrogan G, Bergh J, Cameron D, Goldstein D, et al: Identification of molecular apocrine breast tumours by microarray analysis. Oncogene. 24:4660–4671. 2005. View Article : Google Scholar : PubMed/NCBI
8	Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y and Pietenpol JA: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 121:2750–2767. 2011. View Article : Google Scholar : PubMed/NCBI
9	Fujii R, Hanamura T, Suzuki T, Gohno T, Shibahara Y, Niwa T, Yamaguchi Y, Ohnuki K, Kakugawa Y, Hirakawa H, et al: Increased androgen receptor activity and cell proliferation in aromatase inhibitor-resistant breast carcinoma. J Steroid Biochem Mol Biol. 144:513–522. 2014. View Article : Google Scholar : PubMed/NCBI
10	De Palma M, Biziato D and Petrova TV: Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 17:457–474. 2017. View Article : Google Scholar : PubMed/NCBI
11	Vasiliadou I and Holen I: The role of macrophages in bone metastasis. J Bone Oncol. 2:158–166. 2013. View Article : Google Scholar : PubMed/NCBI
12	Gan L, Qiu Z, Huang J, Li Y, Huang H, Xiang T, Wan J, Hui T, Lin Y, Li H and Ren G: Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway. Int J Biol Sci. 12:1533–1543. 2016. View Article : Google Scholar : PubMed/NCBI
13	Yang J, Li X, Liu X and Liu Y: The role of tumor-associated macrophages in breast carcinoma invasion and metastasis. Int J Clin Exp Pathol. 8:6656–6664. 2015.PubMed/NCBI
14	Li J, He K, Liu P and Xu LX: Iron participated in breast cancer chemoresistance by reinforcing IL-6 paracrine loop. Biochem Biophys Res Commun. 475:154–160. 2016. View Article : Google Scholar : PubMed/NCBI
15	Liu H, Wang J, Zhang M, Xuan Q, Wang Z, Lian X and Zhang Q: Jagged1 promotes aromatase inhibitor resistance by modulating tumor-associated macrophage differentiation in breast cancer patients. Breast Cancer Res Treat. 166:95–107. 2017. View Article : Google Scholar : PubMed/NCBI
16	Gelsomino L, Giordano C, Camera GL, Sisci D, Marsico S, Campana A, Tarallo R, Rinaldi A, Fuqua S, Leggio A, et al: Leptin signaling contributes to aromatase inhibitor resistant breast cancer cell growth and activation of macrophages. Biomolecules. 10:5432020. View Article : Google Scholar : PubMed/NCBI
17	Chanmee T, Ontong P, Konno K and Itano N: Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). 6:1670–1690. 2014. View Article : Google Scholar : PubMed/NCBI
18	Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, et al: Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 41:14–20. 2014. View Article : Google Scholar : PubMed/NCBI
19	Sousa S, Brion R, Lintunen M, Kronqvist P, Sandholm J, Mönkkönen J, Kellokumpu-Lehtinen PL, Lauttia S, Tynninen O, Joensuu H, et al: Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Res. 17:1012015. View Article : Google Scholar : PubMed/NCBI
20	McCrohon JA, Death AK, Nakhla S, Jessup W, Handelsman DJ, Stanley KK and Celermajer DS: Androgen receptor expression is greater in macrophages from male than from female donors. A sex difference with implications for atherogenesis. Circulation. 101:224–226. 2000. View Article : Google Scholar : PubMed/NCBI
21	Huang CK, Pang H, Wang L, Niu Y, Luo J, Chang E, Sparks JD, Lee SO and Chang C: New therapy via targeting androgen receptor in monocytes/macrophages to battle atherosclerosis. Hypertension. 63:1345–1353. 2014. View Article : Google Scholar : PubMed/NCBI
22	Lai JJ, Lai KP, Chuang KH, Chang P, Yu IC, Lin WJ and Chang C: Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-alpha expression. J Clin Invest. 119:3739–3751. 2009. View Article : Google Scholar : PubMed/NCBI
23	Yamaguchi M, Takagi K, Sato A, Miki Y, Miyashita M, Sasano H and Suzuki T: Rac1 activation in human breast carcinoma as a prognostic factor associated with therapeutic resistance. Breast Cancer. 27:919–928. 2020. View Article : Google Scholar : PubMed/NCBI
24	Yamaguchi M, Takagi K, Narita K, Miki Y, Onodera Y, Miyashita M, Sasano H and Suzuki T: Stromal CCL5 promotes breast cancer progression by interacting with ccr3 in tumor cells. Int J Mol Sci. 22:19182021. View Article : Google Scholar : PubMed/NCBI
25	Hamlin IM: Possible host resistance in carcinoma of the breast: A histological study. Br J Cancer. 22:383–401. 1968. View Article : Google Scholar : PubMed/NCBI
26	Hammond ME, Hayes DF, Wolff AC, Mangu PB and Temin S: American society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract. 6:195–197. 2010. View Article : Google Scholar : PubMed/NCBI
27	Takagi K, Miki Y, Onodera Y, Ishida T, Watanabe M, Sasano H and Suzuki T: ARHGAP15 in human breast carcinoma: A potent tumor suppressor regulated by androgens. Int J Mol Sci. 19:E8042018. View Article : Google Scholar
28	Sato A, Takagi K, Miki Y, Yoshimura A, Hara M, Ishida T, Sasano H and Suzuki T: Cytochrome c1 as a favorable prognostic marker in estrogen receptor-positive breast carcinoma. Histol Histopathol. 34:1365–1375. 2019.PubMed/NCBI
29	Vergnes L, Phan J, Stolz A and Reue K: A cluster of eight hydroxysteroid dehydrogenase genes belonging to the aldo-keto reductase supergene family on mouse chromosome 13. J Lipid Res. 44:503–511. 2003. View Article : Google Scholar : PubMed/NCBI
30	Niu Y, Altuwaijri S, Yeh S, Lai KP, Yu S, Chuang KH, Huang SP, Lardy H and Chang C: Targeting the stromal androgen receptor in primary prostate tumors at earlier stages. Proc Natl Acad Sci USA. 105:12188–12193. 2008. View Article : Google Scholar : PubMed/NCBI
31	Cioni B, Zaalberg A, van Beijnum JR, Melis MHM, van Burgsteden J, Muraro MJ, Hooijberg E, Peters D, Hofland I, Lubeck Y, et al: Androgen receptor signalling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion. Nat Commun. 11:44982020. View Article : Google Scholar : PubMed/NCBI
32	Figueroa F, Davicino R, Micalizzi B, Oliveros L and Forneris M: Macrophage secretions modulate the steroidogenesis of polycystic ovary in rats: Effect of testosterone on macrophage pro-inflammatory cytokines. Life Sci. 90:733–739. 2012. View Article : Google Scholar : PubMed/NCBI
33	Levano KS, Jung EH and Kenny PA: Breast cancer subtypes express distinct receptor repertoires for tumor-associated macrophage derived cytokines. Biochem Biophys Res Commun. 411:107–110. 2011. View Article : Google Scholar : PubMed/NCBI
34	Chen LY, Brown PR, Willis WB and Eddy EM: Peritubular myoid cells participate in male mouse spermatogonial stem cell maintenance. Endocrinology. 155:4964–4974. 2014. View Article : Google Scholar : PubMed/NCBI
35	Gwak JM, Jang MH, Kim DI, Seo AN and Park SY: Prognostic value of tumor-associated macrophages according to histologic locations and hormone receptor status in breast cancer. PLoS One. 10:e01257282015. View Article : Google Scholar : PubMed/NCBI
36	Klingen TA, Chen Y, Aas H, Wik E and Akslen LA: Tumor-associated macrophages are strongly related to vascular invasion, non-luminal subtypes, and interval breast cancer. Hum Pathol. 69:72–80. 2017. View Article : Google Scholar : PubMed/NCBI
37	Takagi K, Miki Y, Nagasaki S, Hirakawa H, Onodera Y, Akahira J, Ishida T, Watanabe M, Kimijima I, Hayashi S, et al: Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment. Endocr Relat Cancer. 17:415–430. 2010. View Article : Google Scholar : PubMed/NCBI
38	Yang L and Zhang Y; Tumor-associated macrophages, : From basic research to clinical application. J Hematol Oncol. 10:582017. View Article : Google Scholar : PubMed/NCBI
39	Schneider CP, Schwacha MG, Samy TS, Bland KI and Chaudry IH: Androgen-mediated modulation of macrophage function after trauma-hemorrhage: Central role of 5alpha-dihydrotestosterone. J Appl Physiol (1985). 95:104–112. 2003. View Article : Google Scholar : PubMed/NCBI
40	Zhao R, Wang X, Jiang C, Shi F, Zhu Y, Yang B, Zhuo J, Jing Y, Luo G, Xia S and Han B: Finasteride accelerates prostate wound healing after thulium laser resection through DHT and AR signalling. Cell Prolif. 51:e124152018. View Article : Google Scholar : PubMed/NCBI
41	Hagemann T, Robinson SC, Schulz M, Trümper L, Balkwill FR and Binder C: Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis. 25:1543–1549. 2004. View Article : Google Scholar : PubMed/NCBI
42	Wan S, Zhao E, Kryczek I, Vatan L, Sadovskaya A, Ludema G, Simeone DM, Zou W and Welling TH: Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology. 147:1393–1404. 2014. View Article : Google Scholar : PubMed/NCBI
43	Mohibi S, Mirza S, Band H and Band V: Mouse models of estrogen receptor-positive breast cancer. J Carcinog. 10:352011. View Article : Google Scholar : PubMed/NCBI
44	Pulaski BA and Ostrand-Rosenberg S: Mouse 4T1 breast tumor model. Curr Protoc Immunol. 20:Chapter 20: Unit 20.2. 2001.PubMed/NCBI
45	Cho HJ, Jung JI, Lim DY, Kwon GT, Her S and Park JH and Park JH: Bone marrow-derived, alternatively activated macrophages enhance solid tumor growth and lung metastasis of mammary carcinoma cells in a Balb/C mouse orthotopic model. Breast Cancer Res. 14:R812012. View Article : Google Scholar : PubMed/NCBI
46	Jang JY, Lee JK, Jeon YK and Kim CW: Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization. BMC Cancer. 13:4212013. View Article : Google Scholar : PubMed/NCBI