Immunocytochemical Localization of Sex Steroid Hormone Receptors in Normal Human Mammary Gland

Li, Sijie; Han, Bing; Liu, Guojin; Li, Songyun; Ouellet, Johanne; Labrie, Fernand; Pelletier, Georges

doi:10.1369/jhc.2009.954644

Cited by 44 publications

(30 citation statements)

References 52 publications

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“…Steroid hormone receptors are crucial components of signaling pathways and act as transcription factors to regulate gene expression [38]. Along with their coactivators, these transcription factors play an important role in breast cancer oncogenesis and progression.…”

Section: Discussionmentioning

confidence: 99%

Androgen Receptor Expression and Bicalutamide Antagonize Androgen Receptor Inhibit β-Catenin Transcription Complex in Estrogen Receptor-Negative Breast Cancer

Huang

Han

Liang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Little is known about the potential mechanism of action for androgen receptor (AR) targeting treatment in estrogen receptor (ER)-negative breast cancer. This study aimed to evaluate AR status and its prognosis in four breast cancer subtypes. Bicalutamide has been identified as an AR antagonist and used for treating AR+/ER- breast cancer in a phase II trial. Our studies will clarify its mechanism in breast cancer treatment. Methods: A total of 510 consecutive cases of invasive ductal cancer (IDC) were evaluated in this study. The expression of AR was analyzed by immunohistochemistry and compared with patient survival, and its implications were evaluated in four subtypes of IDC. We examined bicalutamide as an AR antagonist to inhibit proliferation and increased apoptosis in AR+/ER- breast cancer cell lines. We explored the tumor suppressive functions of bicalutamide in vitro and vivo and its related mechanisms in AR+/ER- breast cancer. Results: AR expression was related to that of ER (P<0.001), PR (P<0.001), Her2 (P=0.017), Ki-67(P=0.020) and to four subtypes (P<0.001). AR retained independent prognostic signifcance (P=0.007, ER- cases; P=0.001, ER+ cases; P=0.001, total cases). We found that bicalutamide significantly decreased viability and increased apoptosis in vitro and vivo. The mechanistic analysis revealed that bicalutamide blocked androgen-stimulated oncogenic AR and Wnt/β-catenin signaling and inhibited the growth of AR+/ER- breast cancer. Conclusion: Our studies provide novel insights into bicalutamide as an antagonist of AR function in AR+/ER- breast cancer and reveal the mechanistic basis for targeting AR as a therapeutic opportunity for patients with AR+/ER- breast cancer.

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Section: Discussionmentioning

confidence: 99%

Androgen Receptor Expression and Bicalutamide Antagonize Androgen Receptor Inhibit β-Catenin Transcription Complex in Estrogen Receptor-Negative Breast Cancer

Huang

Han

Liang

et al. 2017

Cell Physiol Biochem

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“…In contrast to the high and widespread expression of ERα in human lobules, murine HS-MECs are reported to be generally found in, at the most, small clusters of a few cells at adulthood (reviewed in [23]). Murine HS-MECs are rarely found dominating the luminal layer, as found in human TDLUs [24], except in nulliparous mice only after exposure to oestrogen and progesterone, as early LA development is characterised by PGR-positive cells dominating early alveolar buds [11].…”

Section: Mec Organization: Species-specific Differencesmentioning

confidence: 95%

Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

Tarulli

Laven-Law

Shakya

et al. 2015

J Mammary Gland Biol Neoplasia

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The hormone-sensing mammary epithelial cell (HS-MEC-expressing oestrogen receptor-alpha (ERα) and progesterone receptor (PGR)) is often represented as being terminally differentiated and lacking significant progenitor activity after puberty. Therefore while able to profoundly influence the proliferation and function of other MEC populations, HS-MECs are purported not to respond to sex hormone signals by engaging in significant cell proliferation during adulthood. This is a convenient and practical simplification that overshadows the sublime, and potentially critical, phenotypic plasticity found within the adult HS-MEC population. This concept is exemplified by the large proportion (~80 %) of human breast cancers expressing PGR and/or ERα, demonstrating that HS-MECs clearly proliferate in the context of breast cancer. Understanding how HS-MEC proliferation and differentiation is driven could be key to unraveling the mechanisms behind uncontrolled HS-MEC proliferation associated with ERα- and/or PGR-positive breast cancers. Herein we review evidence for the existence of a HS-MEC progenitor and the emerging plasticity of the HS-MEC population in general. This is followed by an analysis of hormones other than oestrogen and progesterone that are able to influence HS-MEC proliferation and differentiation: androgens, prolactin and transforming growth factor-beta1.

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“…11,12 It is expressed in the normal human mammary gland, where it predominantly localizes to the luminal or inner layer of epithelial cells lining acini and intralobular ducts. 13,14 The exact role of androgen receptor in normal mammary epithelial biology is unknown. Androgen receptor has been implicated in breast tumorigenesis; however, delineating its precise function has proven difficult, with androgen receptor-mediated androgenic effects shown to both stimulate and inhibit growth of breast cancer cells.…”

mentioning

confidence: 99%

Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer

et al. 2014

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Treatment of triple-negative invasive breast cancers, defined by the absence of estrogen and progesterone receptors and c-erbB2 expression, remains challenging. Androgen receptor, a member of the nuclear receptor superfamily that is involved in signaling pathways regulating cell proliferation, has been implicated in breast tumorigenesis. We immunohistochemically examined the expression of androgen receptor, basal markers (CK14, 34bE12) and EGFR in 699 triple-negative invasive breast cancers in tissue microarrays using the streptavidin-biotin method, and correlated the findings with clinical outcome. Positive androgen receptor expression was defined as staining of 1% or more of tumor cell nuclei. Survival outcomes were estimated with the Kaplan-Meier method and compared between groups with log-rank statistics. Cox proportional hazards models were used to determine the effect of androgen receptor on survival outcomes. Immunohistochemical positivity was observed in 38% of tumors, with the proportion of stained tumor cells ranging from 1 to 95% (mean 29%, median 10%). Androgen receptor expression was inversely associated with histologic grade and mitotic score. CK14, 34bE12 and EGFR confirmed 85% of cases to be basal-like, without significant association of basal-like phenotype with androgen receptor expression. Disease-free survival was significantly better in androgen receptor-positive triple-negative breast cancer, with a trend for improved overall survival. Decreased recurrence likelihood in both triple-negative and basal-like tumors (hazard ratio, 0.704; 95% confidence intervals, 0.498-0.994; P ¼ 0.0464; and hazard ratio, 0.675; 95% confidence intervals, 0.468-0.974; P ¼ 0.0355, respectively) was noted within 5 years of diagnosis but not thereafter. Our study suggests that loss of androgen receptor in triple-negative breast cancers augurs a worse prognosis, including those with basal-like features. More work in elucidating its relationship with mechanisms of progression, as well as trials of targeted treatment for androgen receptor-expressing triple-negative tumors, needs to be performed.

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Immunocytochemical Localization of Sex Steroid Hormone Receptors in Normal Human Mammary Gland

Cited by 44 publications

References 52 publications

Androgen Receptor Expression and Bicalutamide Antagonize Androgen Receptor Inhibit β-Catenin Transcription Complex in Estrogen Receptor-Negative Breast Cancer

Androgen Receptor Expression and Bicalutamide Antagonize Androgen Receptor Inhibit β-Catenin Transcription Complex in Estrogen Receptor-Negative Breast Cancer

Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer

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