Steroid hormones regulate a wide variety of physiological and developmental functions. Traditional steroid hormone signaling acts through nuclear and cytosolic receptors, altering gene transcription and subsequently regulating cellular activity. This is particularly important in hormonally-responsive cancers, where therapies that target classical steroid hormone receptors have become clinical staples in the treatment and management of disease. Much progress has been made in the last decade in detecting novel receptors and elucidating their mechanisms, particularly their rapid signaling effects and subsequent impact on tumorigenesis. Many of these receptors are membrane-bound and lack DNA-binding sites, functionally separating them from their classical cytosolic receptor counterparts. Membrane-bound receptors have been implicated in a number of pathways that disrupt the cell cycle and impact tumorigenesis. Among these are pathways that involve phospholipase D, phospholipase C, and phosphoinositide-3 kinase. The crosstalk between these pathways has been shown to affect apoptosis and proliferation in cardiac cells, osteoblasts, and chondrocytes as well as cancer cells. This review focuses on rapid signaling by 17β-estradiol and 1α,25-dihydroxy vitamin D3 to examine the integrated actions of classical and rapid steroid signaling pathways both in contrast to each other and in concert with other rapid signaling pathways. This new approach lends insight into rapid signaling by steroid hormones and its potential for use in targeted drug therapies that maximize the benefits of traditional steroid hormone-directed therapies while mitigating their less desirable effects.

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17β-estradiol (E2) plays a key role in tumorigenesis by enhancing cell survivability and metastasis through its cytoplasmic receptors. Recently, a variant of estrogen receptor alpha, ERα36 has been implicated as a substantial mediator of E2’s proliferative and anti-apoptotic effects through rapid membrane-associated signaling, and cancers previously regarded as hormone-independent due to the absence of traditional receptors, may in fact be susceptible to E2. Despite rising from a secondary sex organ and having a clear gender disposition, laryngeal cancer is not uniformly accepted as hormone-dependent, even in the face of compelling evidence of E2 responsiveness. The aim of this study was to further elucidate the role of E2 in the tumorigenesis of laryngeal cancer, both in vitro and in vivo. ERα36 presence was evaluated in membranes of the laryngeal carcinoma cell line, Hep2, as well as in laryngeal tumor samples. In vitro, ERα36 was found to mediate rapid activation of protein kinase C and phospholipase D by E2, leading to increased proliferation and protection against chemotherapy-induced apoptosis. Furthermore, in response to E2 activation of ERα36, an upregulation of angiogenic and metastatic factors was observed. Clinical analysis of laryngeal tumors revealed a similar association between the amount of ERα36 and VEGF, and indicated a role in lymph node metastasis. These findings present compelling evidence of ERα36-dependent E2 signaling in laryngeal cancer. Thus, targeting ERα36 may reduce the deleterious effects of E2 in laryngeal cancer, ultimately suggesting the importance of anti-estrogen therapy or the production of novel drugs that specifically target ERα36.

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